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1
Broome, Ann-Marie, David Ryan, and Richard L. Eckert. "S100 Protein Subcellular Localization During Epidermal Differentiation and Psoriasis." Journal of Histochemistry & Cytochemistry 51, no. 5 (May 2003): 675–85. http://dx.doi.org/10.1177/002215540305100513.
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S100 proteins are calcium-activated signaling proteins that interact with target proteins to modulate biological processes. Our present studies compare the level of expression, and cellular localization of S100A7, S100A8, S100A9, S100A10, and S100A11 in normal and psoriatic epidermis. S100A7 and S100A11 are present in the basal and spinous layers in normal epidermis. These proteins appear in the nucleus and cytoplasm in basal cells but are associated with the plasma membrane in spinous cells. S100A10 is present in basal and spinous cells, in the cytoplasm, and is associated with the plasma membrane. S100A8 and S100A9 are absent or are expressed at minimal levels in normal epidermis. In involved psoriatic tissue, S100A10 and S100A11 levels remain unchanged, whereas, S100A7, S100A8, and S100A9 are markedly overexpressed. The pattern of expression and subcellular localization of S100A7 is similar in normal and psoriatic tissue. S100A8 and S100A9 are strongly expressed in the basal and spinous layers in psoriasis-involved tissue. In addition, we demonstrate that S100A7, S100A10, and S100A11 are incorporated into detergent and reducing agent-resistant multimers, suggesting that they are in vivo trans-glutaminase substrates. S100A8 and S100A9 did not form these larger complexes. These results indicate that S100 proteins localize to the plasma membrane in differentiated keratinocytes, suggesting a role in regulating calcium-dependent, membrane-associated events. These studies also indicate, as reported previously, that S100A7, S100A8, and S100A9 expression is markedly altered in psoriasis, suggesting a role for these proteins in disease pathogenesis.
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Mitrović Ajtić, Olivera, Tijana Subotički, Miloš Diklić, Dragoslava Đikić, Milica Vukotić, Teodora Dragojević, Emilija Živković, Darko Antić, and Vladan Čokić. "Regulation of S100As Expression by Inflammatory Cytokines in Chronic Lymphocytic Leukemia." International Journal of Molecular Sciences 23, no. 13 (June 22, 2022): 6952. http://dx.doi.org/10.3390/ijms23136952.
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The calcium-binding proteins S100A4, S100A8, and S100A9 are upregulated in chronic lymphocytic leukemia (CLL), while the S100A9 promotes NF-κB activity during disease progression. The S100-protein family has been involved in several malignancies as mediators of inflammation and proliferation. The hypothesis of our study is that S100A proteins are mediators in signaling pathways associated with inflammation-induced proliferation, such as NF-κB, PI3K/AKT, and JAK/STAT. The mononuclear cells (MNCs) of CLL were treated with proinflammatory IL-6, anti-inflammatory IL-10 cytokines, inhibitors of JAK1/2, NF-κB, and PI3K signaling pathways, to evaluate S100A4, S100A8, S100A9, and S100A12 expression as well as NF-κB activation by qRT-PCR, immunocytochemistry, and immunoblotting. The quantity of S100A4, S100A8, and S100A9 positive cells (p < 0.05) and their protein expression (p < 0.01) were significantly decreased in MNCs of CLL patients compared to healthy controls. The S100A levels were generally increased in CD19+ cells compared to MNCs of CLL. The S100A4 gene expression was significantly stimulated (p < 0.05) by the inhibition of the PI3K/AKT signaling pathway in MNCs. IL-6 stimulated S100A4 and S100A8 protein expression, prevented by the NF-κB and JAK1/2 inhibitors. In contrast, IL-10 reduced S100A8, S100A9, and S100A12 protein expressions in MNCs of CLL. Moreover, IL-10 inhibited activation of NF-κB signaling (4-fold, p < 0.05). In conclusion, inflammation stimulated the S100A protein expression mediated via the proliferation-related signaling and balanced by the cytokines in CLL.
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Peterova, Eva, Jan Bures, Paula Moravkova, and Darina Kohoutova. "Tissue mRNA for S100A4, S100A6, S100A8, S100A9, S100A11 and S100P Proteins in Colorectal Neoplasia: A Pilot Study." Molecules 26, no. 2 (January 14, 2021): 402. http://dx.doi.org/10.3390/molecules26020402.
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S100 proteins are involved in the pathogenesis of sporadic colorectal carcinoma through different mechanisms. The aim of our study was to assess tissue mRNA encoding S100 proteins in patients with non-advanced and advanced colorectal adenoma. Mucosal biopsies were taken from the caecum, transverse colon and rectum during diagnostic and/or therapeutic colonoscopy. Another biopsy was obtained from adenomatous tissue in the advanced adenoma group. The tissue mRNA for each S100 protein (S100A4, S100A6, S100A8, S100A9, S100A11 and S100P) was investigated. Eighteen biopsies were obtained from the healthy mucosa in controls and the non-advanced adenoma group (six individuals in each group) and thirty biopsies in the advanced adenoma group (ten patients). Nine biopsies were obtained from advanced adenoma tissue (9/10 patients). Significant differences in mRNA investigated in the healthy mucosa were identified between (1) controls and the advanced adenoma group for S100A6 (p = 0.012), (2) controls and the non-advanced adenoma group for S100A8 (p = 0.033) and (3) controls and the advanced adenoma group for S100A11 (p = 0.005). In the advanced adenoma group, differences between the healthy mucosa and adenomatous tissue were found in S100A6 (p = 0.002), S100A8 (p = 0.002), S100A9 (p = 0.021) and S100A11 (p = 0.029). Abnormal mRNA expression for different S100 proteins was identified in the pathological adenomatous tissue as well as in the morphologically normal large intestinal mucosa.
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McLachlan, Julia L., Alastair J. Sloan, Anthony J. Smith, Gabriel Landini, and Paul R. Cooper. "S100 and Cytokine Expression in Caries." Infection and Immunity 72, no. 7 (July 2004): 4102–8. http://dx.doi.org/10.1128/iai.72.7.4102-4108.2004.
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ABSTRACT The molecular immune response of the pulpal tissue during chronic carious infection is poorly characterized. Our objective was to examine the expression of potential molecular mediators of pulpal inflammation, correlate their levels with disease severity, and determine the cellular localization of key molecules. Results indicated that there was significantly increased transcriptional activity in carious compared to healthy pulp, and the increase correlated positively with disease severity. Semiquantitative reverse transcriptase PCR analysis in 10 carious and 10 healthy pulpal tissue samples of the S100 family members S100A8, S100A9, S100A10, S100A12, and S100A13; the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-8, IL-6, and epithelial cell-derived neutrophil attractant 78 (ENA-78); and the structural protein collagen-1α indicated that all genes tested, with the exception of S100A10, were more abundantly expressed in carious teeth. In addition, we found that the closer the carious lesion front was to the pulpal chamber the higher the expression was for all genes except S100A10. Multiple-regression analysis identified a significant positive correlation between the expression levels of S100A8 and IL-1β, ENA-78, and IL-6 and between collagen-1α and S100A8, TNF-α, IL-1β, IL-8, IL-6, and ENA-78. Immunohistochemical studies in carious pulpal tissue indicated that S100A8 and the S100A8/S100A9 complex were predominantly expressed by infiltrating neutrophils. Gene expression analyses in immune system cells supported these findings and indicated that bacterial activation of neutrophils caused upregulation of S100A8, S100A9, and S100A13. This study highlights the complex nature of the molecular immune response that occurs during carious infection.
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Roszkowski, Leszek, Bożena Jaszczyk, Magdalena Plebańczyk, and Marzena Ciechomska. "S100A8 and S100A12 Proteins as Biomarkers of High Disease Activity in Patients with Rheumatoid Arthritis That Can Be Regulated by Epigenetic Drugs." International Journal of Molecular Sciences 24, no. 1 (December 31, 2022): 710. http://dx.doi.org/10.3390/ijms24010710.
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Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that is still not well understood in terms of its pathogenesis and presents diagnostic and therapeutic challenges. Monocytes are key players in initiating and maintaining inflammation through the production of pro-inflammatory cytokines and S100 proteins in RA. This study aimed to test a specific DNA methylation inhibitor (RG108) and activator (budesonide) in the regulation of pro-inflammatory mediators—especially the S100 proteins. We also searched for new biomarkers of high disease activity in RA patients. RNA sequencing analysis of healthy controls (HCs) and RA monocytes was performed. Genes such as the S100 family, TNF, and IL-8 were validated by qRT-PCR following DNA-methylation-targeted drug treatment in a monocytic THP-1 cell line. The concentrations of the S100A8, S100A11, and S100A12 proteins in the sera and synovial fluids of RA patients were tested and correlated with clinical parameters. We demonstrated that RA monocytes had significantly increased levels of S100A8, S100A9, S100A11, S100A12, MYD88, JAK3, and IQGAP1 and decreased levels of IL10RA and TGIF1 transcripts. In addition, stimulation of THP-1 cells with budesonide statistically reduced the expression of the S100 family, IL-8, and TNF genes. In contrast, THP-1 cells treated with RG108 had increased levels of the S100 family and TNF genes. We also revealed a significant upregulation of S100A8, S100A11, and S100A12 in RA patients, especially in early RA compared to HC sera. In addition, protein levels of S100A8, S100A11, and S100A12 in RA synovial fluids compared to HC sera were significantly increased. Overall, our data suggest that the S100A8 and S100A12 proteins are strongly elevated during ongoing inflammation, so they could be used as a better biomarker of disease activity than CRP. Interestingly, epigenetic drugs can regulate these S100 proteins, suggesting their potential use in targeting RA inflammation.
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Holmannová, Drahomíra, Barbora Císařová, Pavel Borský, Zdeněk Fiala, Ctirad Andrýs, Květoslava Hamaková, Tereza Švadláková, et al. "Goeckerman Regimen Reduces Alarmin Levels and PASI Score in Paediatric Patients with Psoriasis." Acta Medica (Hradec Kralove, Czech Republic) 64, no. 4 (2021): 204–12. http://dx.doi.org/10.14712/18059694.2022.3.
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Background. Psoriasis is a chronic systemic inflammatory disease with (extra-)cutaneous manifestations. Inflammation is associated with cellular stress and tissue damage which lead to the release of alarmins (signals of danger). Goeckerman regimen (GR) is a highly efficacious treatment consisting of the application of pharmaceutical crude tar and UVB light exposure. The reduction of inflammatory processes in the skin is accompanied by changes in the levels of inflammatory markers - alarmins (HMBG-1, S100A7, S1000A8, S100A9, S100A12, IL-17, IL-22, and IL-33). Methods. The alarmin levels in sera of 19 paediatric patients with psoriasis were determined before and after GR using commercial ELISA kits. The Psoriasis area severity index (PASI) was used to determine the disease severity. Results. GR reduced both PASI and the levels of all measured alarmins. The levels of S100A7, S100A9, IL-22, IL-33, and HMGB-1 were significantly decreased. Positive correlations between IL-22 and PASI, between S100A9 and IL-17, S100A9 and IL-22, and a negative correlation between S100A8 and IL-33 were found. Conclusions. Goeckerman regimen is a very effective, safe and low-cost therapy. We confirmed, it modulates the immune system reactivity, ameliorates the severity of the disease and reduces the levels of alarmins reflecting the presence and intensity of inflammation.
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Leach, Steven T., Hazel M. Mitchell, Carolyn L. Geczy, Philip M. Sherman, and Andrew S. Day. "S100 Calgranulin Proteins S100A8, S100A9 and S100A12 are Expressed in the Inflamed Gastric Mucosa ofHelicobacter Pylori-Infected Children." Canadian Journal of Gastroenterology 22, no. 5 (2008): 461–64. http://dx.doi.org/10.1155/2008/308942.
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The expression of the inflammatory S100 calgranulin proteins (S100A8, S100A9 and S100A12) in normal andHelicobacter pylori-infected gastric mucosa of children were examined. S100A8, S100A9 and S100A12, which were virtually absent in normal gastric mucosa, were highly expressed inH pylori-infected mucosa. This expression correlated with the severity of gastritis (r=0.9422, P<0.05). S100 calgranulins may be involved in bacterial-induced gastritis and may limit bacterial growth.
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Tardif, Mélanie R., Julie Andrea Chapeton-Montes, Alma Posvandzic, Nathalie Pagé, Caroline Gilbert, and Philippe A. Tessier. "Secretion of S100A8, S100A9, and S100A12 by Neutrophils Involves Reactive Oxygen Species and Potassium Efflux." Journal of Immunology Research 2015 (2015): 1–16. http://dx.doi.org/10.1155/2015/296149.
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S100A8/A9 (calprotectin) and S100A12 proinflammatory mediators are found at inflammatory sites and in the serum of patients with inflammatory or autoimmune diseases. These cytoplasmic proteins are secreted by neutrophils at sites of inflammation via alternative secretion pathways of which little is known. This study examined the nature of the stimuli leading to S100A8/A9 and S100A12 secretion as well as the mechanism involved in this alternative secretion pathway. Chemotactic agents, cytokines, and particulate molecules were used to stimulate human neutrophils. MSU crystals, PMA, and H2O2induced the release of S100A8, S100A9, and S100A12 homodimers, as well as S100A8/A9 heterodimer. High concentrations of S100A8/A9 and S100A12 were secreted in response to nanoparticles like MSU, silica, TiO2, fullerene, and single-wall carbon nanotubes as well as in response to microbe-derived molecules, such as zymosan or HKCA. However, neutrophils exposed to the chemotactic factors fMLP failed to secrete S100A8/A9 or S100A12. Secretion of S100A8/A9 was dependent on the production of reactive oxygen species and required K+exchanges through the ATP-sensitive K+channel. Altogether, these findings suggest that S100A12 and S100A8/A9 are secreted independently either via distinct mechanisms of secretion or following the activation of different signal transduction pathways.
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Li, Changyou, Siyuan Li, Changkai Jia, Lingling Yang, Zicheng Song, and Yiqiang Wang. "Low Concentration of S100A8/9 Promotes Angiogenesis-Related Activity of Vascular Endothelial Cells: Bridges among Inflammation, Angiogenesis, and Tumorigenesis?" Mediators of Inflammation 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/248574.
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Previous studies showed that several members of the S100A family are involved in neovascularization and tumor development. This study checked whether low concentrations of S100A8 or S100A9 has any effect on the behaviour of vascular endothelial cells. A human umbilical vascular endothelial cell (HUVEC) line was used to measure vascular endothelial cell bioactivity related to angiogenesis, such as cell proliferation, migration, and vessel formation. In the low concentration range up to 10 μg/mL, either each alone or in combination, S100A8 and S100A9 proteins promoted proliferation of HUVEC cells in a dose-dependent manner. The presence of both proteins in culture showed additive effects over each single protein. Both proteins enhanced HUVEC cells to migrate across the transwell membrane and to form tube-like structures on the Matrigel surface. When mixed in Matrigel and injected subcutaneously in Balb/c mice, both proteins increased vessel development in the gel plugs. Microarray assay of HUVEC cells treated with 10 μg/mL S100A8 revealed that ribosome pathway, pathogenicEscherichia coliinfection pathway, apoptosis, and stress response genes were modulated by S100A8 treatment. We propose that S100A8 and S100A9 proteins from either infiltrating inflammatory cells or tumor cells play an important role in the interplay among inflammation, angiogenesis, and tumorigenesis.
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Wakiya, R., T. Kameda, K. Ueeda, S. Nakashima, H. Shimada, M. F. Mansour, M. Kato, et al. "Hydroxychloroquine modulates elevated expression of S100 proteins in systemic lupus erythematosus." Lupus 28, no. 7 (May 8, 2019): 826–33. http://dx.doi.org/10.1177/0961203319846391.
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Objectives We investigated the effect of hydroxychloroquine (HCQ) on S100A8 and S100A9 serum levels in systemic lupus erythematosus (SLE) patients with low disease activity receiving immunosuppressants. Methods SELENA-SLEDAI, Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) and serum levels of complement factors, anti-dsDNA antibodies, and white blood cell, lymphocyte, and platelet counts were used to evaluate disease activity, cutaneous disease activity, and immunological activity, respectively. Serum S100A8 and S100A9 were measured at HCQ administration and after 3 or 6 months using ELISA. Results S100A8 and S100A9 serum levels were elevated at baseline and the magnitude of decrease from baseline at 3 and 6 months after HCQ administration was greater in patients with renal involvement than in those without (baseline: S100A8, p = 0.034; S100A9, p = 0.0084; decrease: S100A8, p = 0.049; S100A9, p = 0.023). S100 modulation was observed in patients with ( n = 17; S100A8, p = 0.0011; S100A9, p = 0.0002) and without renal involvement ( n = 20; S100A8, p = 0.0056; S100A9, p = 0.0012), and was more apparent in patients with improved CLASI activity scores (improved: S100A8, p = 0.013; S100A9, p = 0.0032; unimproved: S100A8, p = 0.055; S100A9, p = 0.055). No associations were observed for immunological biomarkers. Conclusion HCQ may improve organ involvement in SLE by modulating S100 protein levels, especially in patients with renal or skin involvement.
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Hu, Shao-yan, Ming-ying Zhang, Shui-yan Wu, Dong Wu, Neetika Ashwani, Jian Pan, Hai-long He, Jian-nong Cen, Zi-Xing Chen, and Chien-Shing Chen. "High Transcription Levels Of S100A8 and S100A9 In Acute Myeloid Leukemia Are Predictors For Poor Overall Survival." Blood 122, no. 21 (November 15, 2013): 2610. http://dx.doi.org/10.1182/blood.v122.21.2610.2610.
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Abstract S100A8 and S100A9 are two members of the S100 calcium-binding protein family, preferentially form functional heterodimers of S100A8/S100A9, and have been increasingly recognized as biomarkers in malignancies. Recent proteomic studies revealed that S100A8 and S100A9 played pivotal roles in hematologic malignancies and elevated expression of S100A8/S100A9 implicated in glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia (ALL). In addition, S100A8 proteomic expression in leukemic cells was reported to predict survival in AML patients. However, information on the gene expression level of S100A8 and S100A9 and their clinical correlation in acute myeloid leukemia (AML) is lacking. Using the real-time quantitative RT-PCR, we analyze the transcription levels of S100A8 and S100A9 in AML patient leukemic specimens underwent pre-planned induction chemotherapy. A total of 189 patient cases at different stages of AML (excluding acute promyelocytic leukemia [APL]), including 91 newly diagnosed AML, 64 patient remission marrow specimens and 34 patient specimens as well as 20 controls without leukemia were included in the study collected from the period between 2007 and 2011. Among the cohort of 91 newly diagnosed AML, the over all median OS was 20 months, and the median follow-up for survivors was 24 months (range: 17 to 60 months). There were significant positive correlations of transcription levels between S100A8 and S100A9 in AML patients from different stages. The expression levels of S100A8 and S100A9 in newly diagnosed and relapsed AML patients revealed no significant difference, but were both lower than those in complete remission and control group. Patients with high transcription level of S100A8 and S100A9 were predominantly in AML with myelo-monocytic differentiation (M4, M5) whereas those with low transcription level of S100A8 and S100A9 often showed more immature cytomorphology (M0, M1), erythrocytic or megakaryocytic differentiation. The subgroup of patient with high transcription level of S100A8 could be a predictor for inferior overall survival (OS) (P = 0.0012). High levels of transcription for both S100A8 and S100A9 in de novo AML patients could predict shorter OS than those with low levels after adjustment on their ages at diagnosis (P = 0.003). In a multivariate analysis for OS, high S100A8 transcription was a significant prognostic factor (P =0.001) after analysis adjustment for age (P = 0.019), bone marrow blast percentage (P = 0.04) and cytogenetic classification (P = 0.05) at diagnosis. Using a combination of S100A8 transcription level and cytogenetic risk classification, survival analysis gave result that the new stratification was highly correlated with the OS (P < 0.0001). With significantly different OS, patients from the intermediate-risk group can be divided into two subgroups (IH = cytogenetically intermediate-risk with S100A8 high transcription and IL = cytogenetically intermediate-risk with S100A8 low transcription). Patients from group IL emerged with a probability of OS similar to the cytogenetically favorable-risk group, whereas the survival curve of IH subgroup was close to the unfavorable-risk group. (Figure)FigureRisk stratification of de novo AML patients by a combination of age and cytogenetic characteristics with S100A8 expression levels. 1H = cytogenetically favorable-risk with S100A8 high expression, 1L = cytogenetically favorable-risk with S100A8 low expression, 2H = cytogenetically intermediate-risk with S100A8 high expression, 2L = cytogenetically intermediate-risk with S100A8 low expression, 3H = cytogenetically unfavorable-risk with S100A8 high expression, 3L = cytogenetically unfavorable-risk with S100A8 low expression.Figure. Risk stratification of de novo AML patients by a combination of age and cytogenetic characteristics with S100A8 expression levels. 1H = cytogenetically favorable-risk with S100A8 high expression, 1L = cytogenetically favorable-risk with S100A8 low expression, 2H = cytogenetically intermediate-risk with S100A8 high expression, 2L = cytogenetically intermediate-risk with S100A8 low expression, 3H = cytogenetically unfavorable-risk with S100A8 high expression, 3L = cytogenetically unfavorable-risk with S100A8 low expression. In conclusion, the transcription levels of S100A8 and S100A9 were significantly associated with development and prognosis of AML. Both S100A8 and S100A9 expression levels provided useful clinical information, and more importantly, S100A8 expression level significantly correlates with prognosis in addition to well-known cytogenetic risk factors, and could potentially further refine current stratification of de novo AML patients. Disclosures: No relevant conflicts of interest to declare.
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Barabé, Frédéric, Malika Laouedj, and Philippe Tessier. "Myeloid-Related Protein S100A9 Induces Cellular Differentiation in Acute Myeloid Leukemia through TLR2 and TLR4 Receptors." Blood 126, no. 23 (December 3, 2015): 3858. http://dx.doi.org/10.1182/blood.v126.23.3858.3858.
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Abstract The myeloid-related proteins S100A8 (MRP8) and S100A9 (MRP14) are endogenous alarmins abundantly and constitutively expressed by myeloid cells (neutrophils, monocytes and immature myeloid cells). S100A8 and S100A9 proteins exist as homodimers but also associate to form the heterodimer calprotectin (S100A8/A9) and are up-regulated in several inflammatory diseases and human cancers. In patients with acute myeloid leukemia (AML), the concentration of S100A8/A9 in serum is elevated and the expression of S100A8 correlates with poor prognosis. However, the role of these proteins in hematologic malignancies is largely unknown. Here, we studied the roles of S100A8 and S100A9 in a mouse model ofAML induced by overexpression of Hoxa9 and Meis1 (H9M1). As observed in human, mice developing AML have a substantial increase in S100A8/A9 their serum (5.0µg/ml ± 1.0µg/mL vs 0.5µg/mL ± 0.1µg/mL for the control, p<0.0001). Using S100A8KO and S100A9KO mice, we demonstrated that S100A8/A9 proteins found in the sera are secreted by leukemic cells and not by the micro-environment. To investigate if secreted S100A8 and S100A9 proteins play a role in leukemogenesis, H9M1 AML were transplanted to secondary recipients were treated intraperitoneally (i.p) with anti-S100A8 or anti-S100A9 antibodies. Blocking S100A8 led to a marked delay in leukemia progression and significantly extended survival compared to control immunoglobulins (IgG) (31 days vs 39.5 days, p=0.010) with an increase of the CD11b+ Gr-1+ double positive population (78.8%±1.4 vs 90.1%±3, p=0.038). In contrast, no differences in overall survival were observed between control IgG and anti-S100A9 treated mice. In addition, we demonstrate that anti-S100A8 treatments reduced AML cell proliferation through the G0/G1 cell cycle arrest. Thus, blocking S100A8 reduces leukemogenesis and induced leukemic blast maturation in AML. To further investigate the roles of S100A8 and S100A9 in AML, we treated secondary H9M1 mice with S100A8 or S100A9 proteins i.p three times per week. Interestingly, injection of S100A8 had no effect on AML latency, but S100A9 treatment resulted in significant delays of leukemia symptoms suggesting an anti-leukemic activity (32 days vs 41 days, p=0.0045). The extent of increased survival induced by S100A9 treatment was similar to standard induction chemotherapy using combination of doxorubicin and cytarabine. Furthermore, S100A9 treatment led to significant cell cycle arrest and an increase of mature cells marker CD11band Gr-1 in bone marrow (76.6%± 1.0% vs 94.8 ± 1.2%, p<0.0001). Analysis of leukemic cells morphology confirmed that S100A9 modulates AML cells maturation. Since injection of the S100A9 protein and anti-S100A8 antibody had similar effect on AML progression and cellular differentiation, we postulated that cell differentiation is regulated by the balance between S100A9 and S100A8. To test the hypothesis, cells were cultured in vitro in presence of different ratio of S100A9 on S100A8. At high ratio (S100A9>S100A8), the percentage of CD11b+ Gr-1+ was increased compared to the control suggesting that leukemic cells underwent differentiation. Nevertheless, the augmentation of S100A8 level prevented the increases of CD11b+ Gr-1+ mediated by S100A9. To test the ability of S100A9 protein to promote terminal cell differentiation of human leukemia, human cord blood (CB) CD34+ cells were transduced with retrovirus expressing the oncogene MLL-AF9. In vitro, S100A9 induced a 10-fold up-regulation of CD14 expression in MLL-AF9 cells. More importantly, the increase of CD14 was associated with morphological changes typical of terminal differentiation into monocytes and then macrophages. To determine the receptor(s) involved in regulation of cellular differentiation induced by S100A9 in human AML, we followed CD14 expression in presence of anti-TLR neutralizing antibodies. Blockage of TLR4 and TLR2 prevented the differentiation of human leukemic cells mediated by S100A9. Taken together, we show that increasing the S100A9/S100A8 ratio in murine AML, either by anti-S100A8 antibody or recombinant S100A9 protein, prolong the survival of secondary mice in vivo by inducing differentiation on AML cells. We corroborated these data in human MLL-AF9 cells in vitro and show that S100A9 protein induces terminal differentiation through TLR receptors which could represent a new therapeutic target to explore. Disclosures No relevant conflicts of interest to declare.
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BASIKA, TATIANA, NATALIA MUÑOZ, CECILIA CASARAVILLA, FLORENCIA IRIGOÍN, CARLOS BATTHYÁNY, MARIANA BONILLA, GUSTAVO SALINAS, et al. "Phagocyte-specific S100 proteins in the local response to theEchinococcus granulosuslarva." Parasitology 139, no. 2 (January 5, 2012): 271–83. http://dx.doi.org/10.1017/s003118201100179x.
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SUMMARYInfection by larvalEchinococcus granulosusis usually characterized by tight inflammatory control. However, various degrees of chronic granulomatous inflammation are also observed, reaching a high point in infection of cattle by the most prevalent parasite strain worldwide, which is not well adapted to this host species. In this context, epithelioid and multinucleated giant macrophages surround the parasite, and the secreted products of these cells often associate with the larval wall. The phagocyte-specific S100 proteins, S100A8, S100A9 and S100A12, are important non-conventionally secreted amplifiers of inflammatory responses. We have analysed by proteomics and immunohistochemistry the presence of these proteins at theE. granulosuslarva-host interface. We found that, in the context of inflammatory control as observed in human infections, the S100 proteins are not abundant, but S100A9 and S100A8 can be expressed by eosinophils distal to the parasite. In the granulomatous inflammation context as observed in cattle infections, we found that S100A12 is one of the most abundant host-derived, parasite-associated proteins, while S100A9 and S100A8 are not present at similarly high levels. As expected, S100A12 derives mostly from the epithelioid and multinucleated giant cells. S100A12, as well as cathepsin K and matrix metalloproteinase-9, also expressed byE. granulosus-elicited epithelioid cells, are connected to the Th17 arm of immunity, which may therefore be involved in this granulomatous response.
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Zeng, Meng-Lu, Xian-Jin Zhu, Jin Liu, Peng-Chong Shi, Yan-Li Kang, Zhen Lin, and Ying-Ping Cao. "An Integrated Bioinformatic Analysis of the S100 Gene Family for the Prognosis of Colorectal Cancer." BioMed Research International 2020 (November 26, 2020): 1–15. http://dx.doi.org/10.1155/2020/4746929.
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Background. S100 family genes exclusively encode at least 20 calcium-binding proteins, which possess a wide spectrum of intracellular and extracellular functions in vertebrates. Multiple lines of evidences suggest that dysregulated S100 proteins are associated with human malignancies including colorectal cancer (CRC). However, the diverse expression patterns and prognostic roles of distinct S100 genes in CRC have not been fully elucidated. Methods. In the current study, we analyzed the mRNA expression levels of S100 family genes and proteins and their associations with the survival of CRC patients using the Oncomine analysis and GEPIA databases. Expressions and mutations of S100 family genes were analyzed using the cBioPortal, and protein-protein interaction (PPI) networks of S100 proteins and their mutation-related coexpressed genes were analyzed using STRING and Cytoscape. Results. We observed that the mRNA expression levels of S100A2, S100A3, S100A9, S100A11, and S100P were higher and the level of S100B was lower in CRC tissues than those in normal colon mucosa. A high S100A10 levels was associated with advanced-stage CRC. Results from GEPIA database showed that highly expressed S100A1 was correlated with worse overall survival (OS) and disease-free survival (DFS) and that overexpressions of S100A2 and S100A11 were associated with poor DFS of CRC, indicating that S100A1, S100A2, and S100A11 are potential prognostic markers. Unexpectedly, most of S100 family genes showed no significant prognostic values in CRC. Conclusions. Our findings, though still need to be ascertained, offer novel insights into the prognostic implications of the S100 family in CRC and will inspire more clinical trials to explore potential S100-targeted inhibitors for the treatment of CRC.
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Thurainayagam, Sumita, Viktor Wixler, Johannes Roth, and Thomas Vogl. "Recovery of S100A8 in the absence of S100A9 exacerbates TNFα-mediated psoriatic-like arthritis (IRC4P.462)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 57.15. http://dx.doi.org/10.4049/jimmunol.194.supp.57.15.
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Abstract Psoriasis is a chronic autoimmune disorder and frequently associated with arthritis (PsA). Alarmins S100A8 and S100A9, expressed in granulocytes, monocytes and activated keratinocytes, are highly up-regulated in psoriatic skin and synovium. Although S100a8 mRNA remains unchanged in S100A9-deficient (S100A9-/-) mice, S100A8 protein expression is abrogated, thus generating a functionally double knockout mouse model. In general, S100A9-/- mice show reduced inflammatory activities in several mouse models of infection and inflammation. Recently, we generated ihTNFtgxS100A9-/- mice by crossing doxycycline-inducible human TNFα-transgenic mice (ihTNFtg) with S100A9-/- mice. Unexpectedly, we observed an enhanced disease progression in these mice as evidenced by increased loss of body weight, paw swelling and cartilage destruction and decreased grip strength compared to ihTNFtg mice upon TNFα induction. Interestingly, the enhanced disease progression was associated with re-expression of S100A8 protein upon TNFα induction, observed in bone marrow, blood, skin and nail keratinocytes by IHC staining and optical imaging. We hypothesize that in the absence of its binding partner S100A9, constitutively active S100A8 homodimers aggravate TNFα-mediated psoriatic-like arthritis. Our data indicate a complex S100A8/S100A9 regulatory mechanism of an alarmin-driven inflammation.
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Stewart, Helen J. S., Sabah Chaudry, Asante Crichlow, Freya Luiling Feilding, and Timothy J. T. Chevassut. "BET Inhibition Suppresses S100A8 and S100A9 Expression in Acute Myeloid Leukemia Cells and Synergises with Daunorubicin in Causing Cell Death." Bone Marrow Research 2018 (May 31, 2018): 1–9. http://dx.doi.org/10.1155/2018/5742954.
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S100A8 and S100A9 are both members of the S100 family and have been shown to play roles in myeloid differentiation, autophagy, apoptosis, and chemotherapy resistance. In this study we demonstrate that the BET-bromodomain inhibitor JQ1 causes rapid suppression of S100A8 and S100A9 mRNA and protein in a reversible manner. In addition, we show that JQ1 synergises with daunorubicin in causing AML cell death. Daunorubicin alone causes a dose- and time-dependent increase in S100A8 and S100A9 protein levels in AML cell lines which is overcome by cotreatment with JQ1. This suggests that JQ1 synergises with daunorubicin in causing apoptosis via suppression of S100A8 and S100A9 levels.
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Van Crombruggen, Koen, Thomas Vogl, Claudina Pérez-Novo, Gabriele Holtappels, and Claus Bachert. "Differential release and deposition of S100A8/A9 proteins in inflamed upper airway tissue." European Respiratory Journal 47, no. 1 (October 22, 2015): 264–74. http://dx.doi.org/10.1183/13993003.00159-2015.
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Intracellular Ca2+-binding S100A8/A9 proteins gain novel functions when released during inflammation. The exact outcome of their extracellular function depends on the local tissue environment in which they are released; both anti-inflammatory and pro-inflammatory responses are described, modulating the immune system by binding Toll-like receptor (TLR)-4 or the receptor for advanced glycation end-products (RAGE). However, the contribution of the proteins in the pathophysiology of chronic rhinosinusitis (CRS) remains unclear.Homomeric S100A8 and S100A9, and heteromeric S100A8/A9 proteins were evaluated in CRS with/without nasal polyps (CRSw/sNP) and controls. Functional responses were assessed in polyp tissue stimulated with S100 proteins in the presence of TLR-4 and RAGE blocking antibodies.S100A8, S100A9 and S100A8/A9 protein levels were significantly higher in CRSwNP patients, showing increased deposition on extracellular matrix (ECM) structures of CRSwNP tissue in contrast to CRSsNP and controls. In the presence ofStaphylococcus aureus, S100A8/A9 is released from neutrophils and from the ECM. Extracellular S100A8 and S100A9 proteins induced increased levels of diverse inflammatory mediatorsviaTLR-4 engagement.The inflammatory/remodelling characteristics of CRSwNP specifically allow increased retention of S100A8, S100A9 and S100A8/A9 proteins in the ECM of CRSwNP tissue. Upon release, homodimeric proteins act as a local danger signal inducing inflammatory mediators, predominantlyviaTLR-4 activation.
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Landers-Ramos, Rian Q., Ryan M. Sapp, Emily VandeWater, Jennifer Macko, Shawn Robinson, Yan Wang, Eva R. Chin, Espen E. Spangenburg, Steven J. Prior, and James M. Hagberg. "Investigating the extremes of the continuum of paracrine functions in CD34−/CD31+ CACs across diverse populations." American Journal of Physiology-Heart and Circulatory Physiology 312, no. 1 (January 1, 2017): H162—H172. http://dx.doi.org/10.1152/ajpheart.00342.2016.
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Paracrine function of circulating angiogenic cells (CACs) is thought to contribute to vascular maintenance. We previously identified S100A8 and S100A9 secreted from physically inactive individuals’ CD34–/CD31+ CACs as negative regulators of capillary-like network formation. The purpose of this study was to investigate further the extremes of the continuum of CAC paracrine actions using two distinctly different groups representing “healthy” and “impaired” CAC function. We aimed to determine how capillary-like network formation in human umbilical vein endothelial cells (HUVECs) is affected by S100A8 and S100A9 in concentrations secreted by CACs from different ends of the health spectrum. CD34–/CD31+ CACs were isolated and cultured from 10 impaired function individuals defined as older (50–89 yr), non-ST-elevation myocardial infarction patients and 10 healthy individuals defined as younger (18–35 yr), healthy individuals, and conditioned media (CM) was generated. CM from the impaired function group's CACs significantly diminished network formation compared with CM from the healthy group ( P < 0.05). We identified elevations in S100A8, S100A9, and S100A8/A9 in the CM from the impaired function group ( P < 0.05). Pretreatment of HUVECs with inhibitors to a known S100A8 and S100A9 receptor, Toll-like receptor 4 (TLR4), but not receptor for advanced glycation end products, improved HUVEC network formation ( P < 0.05) compared with CM alone in the impaired function conditions. Exposure of HUVECs to the TLR4 signaling inhibitor also blocked recombinant S100A8- and S100A9-mediated reductions in network formation. Collectively, the results suggest that the mechanisms behind impaired CAC CD34–/CD31+ CM-mediated reductions in capillary-like network formation involve secretion of S100A8 and S100A9 and binding of these proteins to TLR4 receptors on HUVECs. NEW & NOTEWORTHY S100A8 and S100A9 proteins in concentrations secreted by CD34–/CD31+ circulating angiogenic cells (CACs) with impaired function reduce endothelial cell capillary-like network formation. These effects appear to be mediated by Toll-like receptor 4 and are absent with S100A8 and S100A9 in concentrations secreted by healthy CD34–/CD31+ CACs.
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Leukert, Nadja, Clemens Sorg, and Johannes Roth. "Molecular basis of the complex formation between the two calcium-binding proteins S100A8 (MRP8) and S100A9 (MRP14)." Biological Chemistry 386, no. 5 (May 1, 2005): 429–34. http://dx.doi.org/10.1515/bc.2005.051.
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Abstract S100 proteins form characteristic homo- and/or heterodimers that play a role in calcium-mediated signaling. We characterized the formation of the human S100A8/S100A9 heterodimer using the yeast two-hybrid system. Employing site-directed mutagenesis we found that distinct hydrophobic amino acids of helix I/I′ are located at a crucial site of the S100A8/S100A9 dimer interface, whereas conserved residues within helix IV/IV′ are not important for heterodimerization. Furthermore, amino acids Y16 and F68 prevent homodimerization of human S100A8. These data demonstrate for the first time the functional relevance of distinct hydrophobic amino acids for human S100A8/S100A9 complex formation in vivo.
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Delangre, Etienne, Ezia Oppliger, Serkan Berkcan, Monika Gjorgjieva, Marta Correia de Sousa, and Michelangelo Foti. "S100 Proteins in Fatty Liver Disease and Hepatocellular Carcinoma." International Journal of Molecular Sciences 23, no. 19 (September 20, 2022): 11030. http://dx.doi.org/10.3390/ijms231911030.
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Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent and slow progressing hepatic pathology characterized by different stages of increasing severity which can ultimately give rise to the development of hepatocellular carcinoma (HCC). Besides drastic lifestyle changes, few drugs are effective to some extent alleviate NAFLD and HCC remains a poorly curable cancer. Among the deregulated molecular mechanisms promoting NAFLD and HCC, several members of the S100 proteins family appear to play an important role in the development of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and HCC. Specific members of this Ca2+-binding protein family are indeed significantly overexpressed in either parenchymal or non-parenchymal liver cells, where they exert pleiotropic pathological functions driving NAFLD/NASH to severe stages and/or cancer development. The aberrant activity of S100 specific isoforms has also been reported to drive malignancy in liver cancers. Herein, we discuss the implication of several key members of this family, e.g., S100A4, S100A6, S100A8, S100A9 and S100A11, in NAFLD and HCC, with a particular focus on their intracellular versus extracellular functions in different hepatic cell types. Their clinical relevance as non-invasive diagnostic/prognostic biomarkers for the different stages of NAFLD and HCC, or their pharmacological targeting for therapeutic purpose, is further debated.
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Wen, Liting, Yu Ding, Xiaodong Chen, Keyong Tian, Danfeng Li, Kun Liang, and Bo Yue. "Influences of S100A8 and S100A9 on Proliferation of Nasopharyngeal Carcinoma Cells through PI3K/Akt Signaling Pathway." BioMed Research International 2021 (September 24, 2021): 1–7. http://dx.doi.org/10.1155/2021/9917365.
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Objective. To investigate the effects of S100A8 and S100A9 on proliferation in nasopharyngeal carcinoma cells and the regulatory effects of PI3K/Akt signaling pathway. Methods. Nasopharyngeal carcinoma cells (CNE1) were cultured and randomly divided into three groups: control group, S100A8/S100A9 overexpression group, and siRNA S100A8/S100A9 group. CCK-8 method was used to detect the effect of S100A8 and S100A9 on the viability of nasopharyngeal carcinoma cells. The effects of S100A8 and S100A9 on the colony forming ability of nasopharyngeal carcinoma cells were detected by colony forming assay. The effects of S100A8 and S100A9 on the proliferation of nasopharyngeal carcinoma cells were detected by EdU staining. The mRNA levels of PI3K and Akt were detected by RT-PCR. The expression levels of PI3K and Akt in NPC cells were detected by Western blot. Wortmannin, an inhibitor of PI3K/Akt pathway, was used to inhibit the activation of PI3K/Akt pathway. Results. Compared with the control group, the cell viability, the number of plate clones, the positive rate of EdU staining, and the mRNA and protein levels of PI3K and Akt were increased in the overexpression group. Compared with the control group, the cell viability, the number of plate clones, the positive rate of EdU staining, and the mRNA and protein levels of PI3K and Akt were decreased in the siRNA group. After inhibiting the activation of PI3K/Akt pathway, the viability of NPC cells in the overexpression group decreased significantly at 48 h and 72 h, while that in the siRNA group increased significantly. Conclusion. SiRNA S100A8 and S100A9 could inhibit the proliferation of nasopharyngeal carcinoma cells, and the underlying mechanism may be related to the inhibition of PI3K/Akt signaling pathway.
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Serhal, Rim, George Hilal, George Boutros, Joseph Sidaoui, Layal Wardi, Salah Ezzeddine, and Nada Alaaeddine. "Nonalcoholic Steatohepatitis: Involvement of the Telomerase and Proinflammatory Mediators." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/850246.
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Nonalcoholic steatohepatitis or NASH is an excessive accumulation of fat in hepatocytes accompanied by inflammation and hepatic injury. Proinflammatory molecules such as IL-17, CCL20, S100A8, S100A9, and S100A8/A9 have been shown to be implicated in many types of cancer. Telomerase activity has been found to be associated with chronic inflammation and cancer. NASH can progress to fibrosis then cirrhosis and finally to hepatocellular carcinoma (HCC). Our objective is to try to find a relation between inflammation and the progression of NASH into HCC. We found that there was a significant elevation in the telomerase activity, detected by real-time PCR, between NASH and fibrotic NASH in the liver biopsies of patients. The expression of S100A8, S100A9, S100A8/A9, CCL20, and IL-17, detected by ELISA, is significantly increased in NASH patients with fibrosis in comparison with controls. But, in NASH patients, S100A9, S100A8/A9, and IL-17 only are significantly elevated in comparison with controls. The same, on the mRNA level, expression of IL-17, detected by RT-PCR, is significantly elevated in NASH patients in comparison with controls. Therefore, there is a direct link between the expression of IL-17, CCL20, telomerase, S100A8, and S100A9 in the fibrotic condition and the progression towards cancer.
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Schiopu, Alexandru, and Ovidiu S. Cotoi. "S100A8 and S100A9: DAMPs at the Crossroads between Innate Immunity, Traditional Risk Factors, and Cardiovascular Disease." Mediators of Inflammation 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/828354.
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Amplification of innate immune responses by endogenous danger-associated molecular patterns (DAMPs) promotes inflammation. The involvement of S100A8 and S100A9, DAMPs belonging to the S100 calgranulin family, in the pathogenesis of cardiovascular disease is attracting an increasing amount of interest. S100A8 and S100A9 (also termed MRP8 and MRP14) preferentially form the S100A8/A9 heterodimer (MRP8/14 or calprotectin) and are constitutively expressed in myeloid cells. The levels of circulating S100A8/A9 in humans strongly correlate to blood neutrophil counts and are increased by traditional cardiovascular risk factors such as smoking, obesity, hyperglycemia, and dyslipidemia. S100A8/A9 is an endogenous ligand of toll-like receptor 4 (TLR4) and of the receptor for advanced glycation end products (RAGE) and has been shown to promote atherogenesis in mice. In humans, S100A8/A9 correlates with the extent of coronary and carotid atherosclerosis and with a vulnerable plaque phenotype. S100A8/A9 is locally released following myocardial infarction and amplifies the inflammatory responses associated with myocardial ischemia/reperfusion injury. Elevated plasma levels of S100A8/A9 are associated with increased risk of future coronary events in healthy individuals and in myocardial infarction survivors. Thus, S100A8/A9 might represent a useful biomarker and therapeutic target in cardiovascular disease. Importantly, S100A8/A9 blockers have been developed and are approved for clinical testing.
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Zhou, Yang, Justine Hann, Véronique Schenten, Sébastien Plançon, Jean-Luc Bueb, Fabrice Tolle, and Sabrina Bréchard. "Role of S100A8/A9 for Cytokine Secretion, Revealed in Neutrophils Derived from ER-Hoxb8 Progenitors." International Journal of Molecular Sciences 22, no. 16 (August 17, 2021): 8845. http://dx.doi.org/10.3390/ijms22168845.
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S100A9, a Ca2+-binding protein, is tightly associated to neutrophil pro-inflammatory functions when forming a heterodimer with its S100A8 partner. Upon secretion into the extracellular environment, these proteins behave like damage-associated molecular pattern molecules, which actively participate in the amplification of the inflammation process by recruitment and activation of pro-inflammatory cells. Intracellular functions have also been attributed to the S100A8/A9 complex, notably its ability to regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. However, the complete functional spectrum of S100A8/A9 at the intracellular level is far from being understood. In this context, we here investigated the possibility that the absence of intracellular S100A8/A9 is involved in cytokine secretion. To overcome the difficulty of genetically modifying neutrophils, we used murine neutrophils derived from wild-type and S100A9−/− Hoxb8 immortalized myeloid progenitors. After confirming that differentiated Hoxb8 neutrophil-like cells are a suitable model to study neutrophil functions, our data show that absence of S100A8/A9 led to a dysregulation of cytokine secretion after lipopolysaccharide (LPS) stimulation. Furthermore, we demonstrate that S100A8/A9-induced cytokine secretion was regulated by the nuclear factor kappa B (NF-κB) pathway. These results were confirmed in human differentiated HL-60 cells, in which S100A9 was inhibited by shRNAs. Finally, our results indicate that the degranulation process could be involved in the regulation of cytokine secretion by S100A8/A9.
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Li, Yulin, Boya Chen, Xinying Yang, Congcong Zhang, Yao Jiao, Ping Li, Yan Liu, et al. "S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic/Reperfusion Injury." Circulation 140, no. 9 (August 27, 2019): 751–64. http://dx.doi.org/10.1161/circulationaha.118.039262.
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Background: Myocardial ischemia-reperfusion (MI/R) injury is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key MI/R mediators to initiate MI/R injury. Methods: We used a dynamic transcriptome analysis of mouse heart exposed to various MI/R periods to identify S100a8/a9 as an early mediator. Using loss/gain-of-function approaches to understand the role of S100a8/a9 in MI/R injury, we explored the mechanisms through transcriptome and functional experiment. Dynamic serum S100a8/a9 levels were measured in patients with acute myocardial infarction before and after percutaneous coronary intervention. Patients were prospectively followed for the occurrence of major adverse cardiovascular events. Results: S100a8/a9 was identified as the most significantly upregulated gene during the early reperfusion stage. Knockout of S100a9 markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of S100a9 exacerbated MI/R injury. Transcriptome/functional studies revealed that S100a8/a9 caused mitochondrial respiratory dysfunction in cardiomyocytes. Mechanistically, S100a8/a9 downregulated NDUF gene expression with subsequent mitochondrial complex I inhibition via Toll-like receptor 4/Erk–mediated Pparg coactivator 1 alpha/nuclear respiratory factor 1 signaling suppression. Administration of S100a9 neutralizing antibody significantly reduced MI/R injury and improved cardiac function. Finally, we demonstrated that serum S100a8/a9 levels were significantly increased 1 day after percutaneous coronary intervention in patients with acute myocardial infarction, and elevated S100a8/a9 levels were associated with the incidence of major adverse cardiovascular events. Conclusions: Our study identified S100a8/a9 as a master regulator causing cardiomyocyte death in the early stage of MI/R injury via the suppression of mitochondrial function. Targeting S100a8/a9-intiated signaling may represent a novel therapeutic intervention against MI/R injury. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03752515
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Joshi, Abhishek, Lukas E. Schmidt, Sean A. Burnap, Ruifang Lu, Melissa V. Chan, Paul C. Armstrong, Ferheen Baig, et al. "Neutrophil-Derived Protein S100A8/A9 Alters the Platelet Proteome in Acute Myocardial Infarction and Is Associated With Changes in Platelet Reactivity." Arteriosclerosis, Thrombosis, and Vascular Biology 42, no. 1 (January 2022): 49–62. http://dx.doi.org/10.1161/atvbaha.121.317113.
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Objective: Platelets are central to acute myocardial infarction (MI). How the platelet proteome is altered during MI is unknown. We sought to describe changes in the platelet proteome during MI and identify corresponding functional consequences. Approach and Results: Platelets from patients experiencing ST-segment–elevation MI (STEMI) before and 3 days after treatment (n=30) and matched patients with severe stable coronary artery disease before and 3 days after coronary artery bypass grafting (n=25) underwent quantitative proteomic analysis. Elevations in the proteins S100A8 and S100A9 were detected at the time of STEMI compared with stable coronary artery disease (S100A8: FC, 2.00; false discovery rate, 0.05; S100A9: FC, 2.28; false discovery rate, 0.005). During STEMI, only S100A8 mRNA and protein levels were correlated in platelets ( R =0.46, P =0.012). To determine whether de novo protein synthesis occurs, activated platelets were incubated with 13C-labeled amino acids for 24 hours and analyzed by mass spectrometry. No incorporation was confidently detected. Platelet S100A8 and S100A9 was strongly correlated with neutrophil abundance at the time of STEMI. When isolated platelets and neutrophils were coincubated under quiescent and activated conditions, release of S100A8 from neutrophils resulted in uptake of S100A8 by platelets. Neutrophils released S100A8/A9 as free heterodimer, rather than in vesicles or extracellular traps. In the community-based Bruneck study (n=338), plasma S100A8/A9 was inversely associated with platelet reactivity—an effect abrogated by aspirin. Conclusions: Leukocyte-to-platelet protein transfer may occur in a thromboinflammatory environment such as STEMI. Plasma S100A8/A9 was negatively associated with platelet reactivity. These findings highlight neutrophils as potential modifiers for thrombotic therapies in coronary artery disease.
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Takagi, Ryosuke, Eijiro Sakamoto, Jun-ichi Kido, Yuji Inagaki, Yuka Hiroshima, Koji Naruishi, and Hiromichi Yumoto. "S100A9 Increases IL-6 and RANKL Expressions through MAPKs and STAT3 Signaling Pathways in Osteocyte-Like Cells." BioMed Research International 2020 (February 20, 2020): 1–12. http://dx.doi.org/10.1155/2020/7149408.
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Objective. Calprotectin is a heterocomplex of S100A8 and S100A9 and is mainly secreted from neutrophils, monocytes, and chondrocytes in inflammatory condition. Calprotectin binds to RAGE and TLR4 and induces the expression of proinflammatory chemokines and cytokines in various cells. Periodontitis is a chronic inflammatory disease that leads to gingival inflammation and alveolar bone resorption. Calprotectin levels in gingival crevicular fluid of periodontitis patients are higher than healthy patients. In the present study, the effects of S100A8 and S100A9 on the expressions of proinflammatory cytokines and bone metabolism-related factors in mouse osteocyte-like cells (MLO-Y4-A2) were investigated. Design. MLO-Y4-A2 cells were treated with S100A8 and S100A9, and the expressions of RAGE, TLR4, RANKL, and several inflammatory cytokines were analyzed by PCR and Western blotting or ELISA methods. To investigate the intracellular signaling pathways, phosphorylation of MAPK and STAT3 was determined by Western blotting, and chemical specific inhibitors and siRNAs were used. Results. Expressions of IL-6 and RANKL were increased by treatment with S100A9 but not S100A8. However, both S100A8 and S100A9 did not change expression of IL-1β, IL-8, and TNF-α. Although RAGE and TLR4 expressions were not upregulated by S100A9 treatment, transfection of siRNA for RAGE and TLR4 significantly decreased IL-6 and RANKL expressions. In addition, S100A9 activated p38, ERK, and STAT3 signaling pathways, and inhibitors for these factors significantly decreased S100A9-induced IL-6 and RANKL expressions. Conclusions. These results indicated that S100A9 induces IL-6 and RANKL production via engagement with RAGE and TLR4 signalings in osteocytes and suggested that S100A9 may play important roles in the periodontal alveolar bone destruction.
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Yano, Junko, Glen E. Palmer, Karen E. Eberle, Brian M. Peters, Thomas Vogl, Andrew N. McKenzie, and Paul L. Fidel. "Vaginal Epithelial Cell-Derived S100 Alarmins Induced by Candida albicans via Pattern Recognition Receptor Interactions Are Sufficient but Not Necessary for the Acute Neutrophil Response during Experimental Vaginal Candidiasis." Infection and Immunity 82, no. 2 (December 9, 2013): 783–92. http://dx.doi.org/10.1128/iai.00861-13.
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ABSTRACTVulvovaginal candidiasis (VVC), caused byCandida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response toC. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previousin vitrodata and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluatedin vitroorin vivoin the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression andC. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR-deficient mice. Results revealed that, consistent with previously reportedin vitrodata, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxisin vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9−/−mice, had no effect on the PMN responsein vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction inC. albicans-induced S100A8/S100A9 mRNAsin vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response toC. albicansinvolves PRRs in addition to SIGNR1 and TLR4, or other induction pathways.
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Hagelstein, Jill, Pauline Schneider, Jasper de Boer, Esther Hulleman, Owen Williams, Rob Pieters, and Ronald W. Stam. "High Expression of the Ca2+-Binding Proteins S100A8 and S100A9 Cause Glucocorticoid Resistance in MLL-Rearranged Infant Acute Lymphoblastic Leukemia." Blood 114, no. 22 (November 20, 2009): 729. http://dx.doi.org/10.1182/blood.v114.22.729.729.
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Abstract Abstract 729 MLL-rearranged Acute Lymphoblastic Leukemia (ALL) in infants (i.e. children <1 year of age) represents an aggressive and difficult to treat type of leukemia, displaying cellular resistance to several chemotherapeutics, especially to glucocorticoids like prednisolone. As prednisolone response is highly predictive for clinical outcome, it is of utmost importance to unravel the mechanism underlying resistance to this drug. To gain insights in the prednisolone resistance mechanism, we compared gene expression profiles (Affymetrix HU133plus2) from prednisolone-resistant and prednisolone-sensitive MLL-rearranged infant ALL patients. This gene signature revealed that multiple genes involved in calcium signaling were up-regulated in prednisolone-resistant samples. Most pronounced up-regulation was observed for the S100 protein family members S100A8 and S100A9, which are calcium-binding proteins, that function in a complex. Quantitative RT-PCR (TaqMan) analyses confirmed that S100A8 and S100A9 mRNA expression was ∼100-fold higher in prednisolone-resistant cells compared to patients sensitive to this drug (p=0.008). Glucocorticoids are known to induce apoptosis by releasing Ca2+ from the endoplasmic reticulum (ER) into the cytosol and towards the mitochondria. Within mitochondria, elevated Ca2+ levels induce cytochrome c release, triggering apoptosis. Since S100A8/A9 are capable of binding free cytosolic Ca2+, we hypothesized that over-representation of these cytosolic proteins may prevent Ca2+ to reach the mitochondria and forestall apoptosis. To test our hypothesis, we first co-incubated prednisolone-sensitive MLL-rearranged ALL cells with prednisolone and EGTA or BAPTA-AM. Both agents represent Ca2+chelators and scavenge free cytosolic Ca2+, thereby mimicking the Ca2+binding by S100A8/A9. Flow cytometry analyses showed that both EGTA and BAPTA-AM inhibited the free cytosolic calcium released by prednisolone. Cytotoxicity tests demonstrated that these prednisolone-sensitive cells became more resistant to prednisolone after co-incubation with either EGTA or BAPTA-AM. Next we asked whether enforced over-expression (using retroviral expression vectors) of S100A8 and/or S100A9 in prednisolone-sensitive MLL-rearranged ALL cells could also inhibit free cytosolic Ca2+and induce prednisolone resistance. Indeed, both S100A8 and S100A9 were capable of binding free cytosolic Ca2+ released by prednisolone, accompanied by a 30-40% increase in cell survival when either S100A8 or S100A9 were over-expressed alone. Simultaneous over-expression of both S100A8 and S100A9 almost completely reversed the prednisolone-sensitive into a prednisolone-resistance phenotype. In conclusion, these findings implicate that high expression of S100A8 and S100A9 contributes to prednisolone resistance in MLL-rearranged infant ALL. Disclosures: No relevant conflicts of interest to declare.
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Argyris, P. P., Z. M. Slama, K. F. Ross, A. Khammanivong, and M. C. Herzberg. "Calprotectin and the Initiation and Progression of Head and Neck Cancer." Journal of Dental Research 97, no. 6 (February 14, 2018): 674–82. http://dx.doi.org/10.1177/0022034518756330.
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Calprotectin (S100A8/A9), a heterodimeric complex of calcium-binding proteins S100A8 and S100A9, is encoded by genes mapping to the chromosomal locus 1q21.3 of the epidermal differentiation complex. Whereas extracellular calprotectin shows proinflammatory and antimicrobial properties by signaling through RAGE and TLR4, intracytoplasmic S100A8/A9 appears to be important for cellular development, maintenance, and survival. S100A8/A9 is constitutively expressed in myeloid cells and the stratified mucosal epithelia lining the oropharyngeal and genitourinary mucosae. While upregulated in adenocarcinomas and other cancers, calprotectin mRNA and protein levels decline in head and neck squamous cell carcinoma (HNSCC). S100A8/A9 is also lost during head and neck preneoplasia (dysplasia). Calprotectin decrease does not correlate with the clinical stage (TNM) of HNSCC. When expressed in carcinoma cells, S100A8/A9 downregulates matrix metalloproteinase 2 expression and inhibits invasion and migration in vitro. S100A8/A9 regulates cell cycle progression and decelerates cancer cell proliferation by arresting at the G2/M checkpoint in a protein phosphatase 2α–dependent manner. In HNSCC, S100A8 and S100A9 coregulate with gene networks controlling cellular development and differentiation, cell-to-cell signaling, and cell morphology, while S100A8/A9 appears to downregulate expression of invasion- and tumorigenesis-associated genes. Indeed, tumor formation capacity is attenuated in S100A8/A9-expressing carcinoma cells in vivo. Hence, intracellular calprotectin appears to function as a tumor suppressor in head and neck carcinogenesis. When compared with S100A8/A9-low HNSCC based on analysis of TCGA, S100A8/A9-high HNSCC shows significant upregulation of apoptosis-related genes, including multiple caspases. Accordingly, S100A8/A9 facilitates DNA damage responses in HNSCC, promotes apoptotic cell death, and confers sensitivity to cisplatin and X-radiation in vitro. In the tumor milieu, loss of S100A8/A9 strongly associates with poor squamous differentiation and higher tumor grading, EGFR upregulation, increased DNA methylation, and, finally, poorer overall survival for patients with HNSCC. Hence, intracellular calprotectin shows a multifaceted protective role against the development of HNSCC.
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Tydén, H., C. Lood, B. Gullstrand, A. Jönsen, F. Ivars, T. Leanderson, and A. A. Bengtsson. "Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus." Lupus 26, no. 2 (July 19, 2016): 139–49. http://dx.doi.org/10.1177/0961203316655208.
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Objectives Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs. Methods Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Serum-mediated phagocytosis of NCs by PMNs was analysed by flow cytometry. Clinical data were recorded at time points of blood sampling. Results Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity ( p = 0.01 and p = 0.008, respectively). Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies ( p = 0.01) and glomerulonephritis before treatment ( p = 0.02). Immunosuppressive therapy was associated with a reduction of S100A8/A9 serum levels ( p = 0.002). The ability of serum to support phagocytosis of NCs by PMNs was related to increased S100A8/A9 levels ( p = 0.01). Conclusions Elevated serum levels of S100A8/A9 may be used to monitor disease activity and response to treatment in SLE patients, especially in patients with glomerulonephritis. S100A12 may be a marker of disease activity in SLE. Increased S100A8/A9 levels may reflect immune-pathological processes involving phagocytosis of immune complexes by PMNs.
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Zou, Xianqiong, Brent S. Sorenson, Karen F. Ross, and Mark C. Herzberg. "Augmentation of Epithelial Resistance to Invading Bacteria by Using mRNA Transfections." Infection and Immunity 81, no. 11 (August 12, 2013): 3975–83. http://dx.doi.org/10.1128/iai.00539-13.
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ABSTRACTTo protect against invading bacteria, oral epithelial cells appear to use two effector antimicrobial peptides (AMPs): calprotectin (S100A8-S100A9 heterodimer [S100A8/A9]) in the cytosol and cathelicidin antimicrobial protein (CAMP) in endosomes. We sought to learn whether innate immunity might be augmented benignly to increase resistance against invasive bacteria. Epithelial cells were transiently transfected with mRNA constructs containing either theCAMP,S100A8, andS100A9open reading frames,A8-IRES-A9(fusion sequence), orA8-nIRES-A9(fusion with native internal ribosome entry site [IRES] sequence). CAMP, S100A8, and S100A9 protein levels generally peaked between 16 and 44 h after mRNA transfection, depending on the construct; CAMP was processed to LL-37 over time. Following transfection with the respective mRNAs, CAMP and S100A8/A9 each independently increased resistance of epithelial cells to invasion byListeriaandSalmonellafor up to 48 h; tandem S100A8/A9 constructs were also effective. Cotransfection to express S100A8/A9 and CAMP together augmented resistance, but synergy was not seen. Independent of the new proteins produced, transfection reduced cell viability after 48 h by 20%, with only 2% attributable to apoptosis. Taken together, these results suggest that epithelial cell resistance to invasive pathogens can be augmented by transient transfection of antimicrobial mRNAs into epithelial cells.
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BARDAKCI, Okan, Murat DAŞ, Hilal ŞEHİTOĞLU, Ece ÜNAL ÇETİN, Ünzile ATALAY, Uğur KÜÇÜK, Fatih KAMIŞ, Alpaslan TANOĞLU, and Yavuz BEYAZIT. "The diagnostic value of calcium binding protein S100A8/A9 and S100A12 in acute pancreatitis." Journal of Health Sciences and Medicine 5, no. 3 (May 30, 2022): 844–49. http://dx.doi.org/10.32322/jhsm.1096501.
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Background: S100A8/A9 and S100A12 which are the major calcium-binding proinflammatory proteins secreted by granulocytes, has been proposed to be related to distinct disease states of inflammatory origin. This study aims to explore the circulating levels of S100A8/A9 and S100A12 in acute pancreatitis (AP) and reveal their relationship with conventional inflammatory markers.
Material and Method: Serum S100A8/A9 and S100A12 were determined in AP patients (male/female: 17/13) by using a specific enzyme-linked immunosorbent assay (ELISA) method at both onset and remission and in 30 healthy controls (male/female: 17/13).
Results: Significantly higher S100A8/A9 and S100A12 levels were found in AP patients compared to healthy controls (p
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Thames, Brittany E., James W. Barr, Jan S. Suchodolski, Jörg M. Steiner, and Romy M. Heilmann. "Prospective evaluation of S100A12 and S100A8/A9 (calprotectin) in dogs with sepsis or the systemic inflammatory response syndrome." Journal of Veterinary Diagnostic Investigation 31, no. 4 (June 6, 2019): 645–51. http://dx.doi.org/10.1177/1040638719856655.
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Pattern recognition receptors (e.g., S100A12 or S100A8/A9) hold promise as inflammatory biomarkers. We prospectively determined and compared serum S100A12 and S100A8/A9 concentrations in dogs with sepsis ( n = 11) or systemic inflammatory response syndrome (SIRS; n = 8) over a 3-d period with each other, healthy controls ( n = 50), and other clinical and clinicopathologic variables. Serum S100A12 and S100A8/A9 concentrations were significantly higher in dogs with sepsis or SIRS (all p < 0.05) at the time of hospital admission (day 1) compared to healthy controls, with no differences between patient groups. However, septic dogs had significantly lower serum S100A12 concentrations on day 2 and day 3 (both p < 0.05) compared to dogs with SIRS. Likewise, dogs with sepsis had significantly lower S100A8/A9 concentrations on day 2 ( p < 0.05). Neither serum S100A12 nor S100A8/A9 concentrations were associated with survival to discharge. Our results suggest a differential expression of the S100/calgranulins between dogs with sepsis and those with SIRS. Serum S100A12 or S100A8/A9 concentration at the time of hospital admission did not differentiate dogs with sepsis from those with SIRS, but the trend of S100/calgranulin concentrations during the following 24–48 h may be a useful surrogate marker for differentiating sepsis from SIRS.
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Moravkova, Paula, Darina Kohoutova, Jaroslava Vavrova, and Jan Bures. "Serum S100A6, S100A8, S100A9 and S100A11 proteins in colorectal neoplasia: results of a single centre prospective study." Scandinavian Journal of Clinical and Laboratory Investigation 80, no. 3 (December 19, 2019): 173–78. http://dx.doi.org/10.1080/00365513.2019.1704050.
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Moravkova, Paula, Darina Kohoutova, Jaroslava Vávrová, and Jan Bures. "Tu1943 - Serum S100A6, S100A8, S100A9 and S100A11 in Colorectal Neoplasia: Results of a Single Centre Prospective Study." Gastroenterology 154, no. 6 (May 2018): S—1060—S—1061. http://dx.doi.org/10.1016/s0016-5085(18)33546-7.
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Mondet, Julie, Simon Chevalier, and Pascal Mossuz. "Pathogenic Roles of S100A8 and S100A9 Proteins in Acute Myeloid and Lymphoid Leukemia: Clinical and Therapeutic Impacts." Molecules 26, no. 5 (March 2, 2021): 1323. http://dx.doi.org/10.3390/molecules26051323.
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Deregulations of the expression of the S100A8 and S100A9 genes and/or proteins, as well as changes in their plasma levels or their levels of secretion in the bone marrow microenvironment, are frequently observed in acute myeloblastic leukemias (AML) and acute lymphoblastic leukemias (ALL). These deregulations impact the prognosis of patients through various mechanisms of cellular or extracellular regulation of the viability of leukemic cells. In particular, S100A8 and S100A9 in monomeric, homodimeric, or heterodimeric forms are able to modulate the survival and the sensitivity to chemotherapy of leukemic clones through their action on the regulation of intracellular calcium, on oxidative stress, on the activation of apoptosis, and thanks to their implications, on cell death regulation by autophagy and pyroptosis. Moreover, biologic effects of S100A8/9 via both TLR4 and RAGE on hematopoietic stem cells contribute to the selection and expansion of leukemic clones by excretion of proinflammatory cytokines and/or immune regulation. Hence, the therapeutic targeting of S100A8 and S100A9 appears to be a promising way to improve treatment efficiency in acute leukemias.
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Crombruggen, Koen, Gabriele Holtappels, Thomas Vogl, and Claus Bachert. "S100A8, S100A9 and S100A8/9 in Chronic Rhinosinusitis with Nasal Polyps." Annals of Paediatric Rheumatology 1 (2012): 17. http://dx.doi.org/10.5455/apr.20121129010017.
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Guo, Li, Ben Berger, Jesse W. Rowley, Neal D. Tolley, Bhanu Kanth Manne, Juan Su, Sikui Shen, et al. "Increased Platelet S100A8/S100A9 Associated with Vasculitis in Granulomatosis with Polyangiitis (GPA)." Blood 138, Supplement 1 (November 5, 2021): 3142. http://dx.doi.org/10.1182/blood-2021-152291.
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Abstract Granulomatosis with polyangiitis (GPA), formerly known as Wegener's Granulomatosis, is characterized by vasculitis that predominantly affects small- and medium-sized blood vessels in the sinuses, lungs, and kidneys. In addition to vascular inflammation, GPA is also characterized by an increased risk of thrombosis. The role of platelets in GPA pathogenesis remains incompletely understood. We aimed to better understand the changes in platelet gene expression and function in patients with GPA. Forty-two patients diagnosed with GPA (n=9 with active GPA and n=33 with GPA in remission) and 25 healthy, age-, gender-, and race-matched donors were enrolled. Patients with GPA showed typical disease manifestations, with an average Birmingham Vasculitis Activity Score of 1.6 (Mean±SD 1.6±3.5). One sixth of GPA patients (7/42) had a history of thrombosis. When stimulated with thrombin receptor activating peptide (TRAP, 50nM), platelets from patients with GPA showed significantly increased expression of P-selectin as compared to healthy controls (P-selectin+% Mean±SEM: Healthy 15.50±1.84 vs GPA 25.71±16.05, P<0.05). This suggests increased platelet activation in GPA, consistent with previous findings of increased platelet aggregation in vitro in GPA. In addition, released chemokines sCD40L and platelet-derived growth factor (PDGF) by activated platelets were increased in patients with GPA when we measured the cytokines in the platelet poor plasma using the Miliplex human cytokine Assay [sCD40L (ng/mL) Mean±SEM: Healthy 63.05±6.63 vs GPA 100.40±11.86, P<0.05, PDGF-AA (pg/mL) Mean±SEM: Healthy 137.50±46.52 vs GPA 357.30±79.65, P=0.052]. Next, we performed RNA-sequencing on platelets from GPA patients (n=8, 3 with active GPA disease and 5 in remission) and, for comparison, 4 healthy donors. We identified 75 genes that were significantly differentially expressed between GPA patients and healthy donors. The top 30 genes are listed in Figure 1A. S100A8 and S100A9 were the top two significantly differentially expressed transcripts in patients with GPA (Fig. 1B). These two genes encode proteins that form a heterodimer S100A8/S100A9 (commonly known as calprotectin) known to be increased in the plasma of GPA patients and associated with disease activity. Interestingly, platelets have not been identified as the cellular source of plasma calprotectin in GPA previously. Significantly increased RNA and protein expression of S100A8 and S100A9 in GPA patients was independently validated by qRT-PCR and immunoblot, respectively. The mRNA expression of S100A8 and S100A9 in platelets were significantly correlated with p-ANCA and anti-MPO antibodies, indicating platelet S100A8/S100A9 promotes neutrophil activation and inflammation (Mann-Whitney nonparametric test, P<0.05). As previously reported, plasma levels of calprotectin were also increased in GPA patients. To further evaluate if plateletS100A8/S100A9 mediates endothelial inflammation and vasculitis, we co-cultured platelets activated with thrombin (which increases S100A8/S100A9 secretion) with endothelial cells in the presence or absence of an anti-S100A8/S100A9 blocking antibody. Activated platelets triggered endothelial cell inflammation (e.g., increased expression of ICAM-1) that was significantly reduced when S100A8/S100A9 was blocked. In summary, the platelet transcriptome is altered in patients with GPA, with S100A8 and S100A9 being the top upregulated genes. Platelet functional responses are enhanced in patients with GPA, and our data suggests that increased plasma calprotectin levels in GPA patients may be platelet derived. Platelets and platelet S100A8/S100A9 appear to mediate vascular inflammation and thrombosis in GPA. Figure 1 Figure 1. Disclosures Rondina: Novartis: Research Funding; Platelet Biogenesis: Membership on an entity's Board of Directors or advisory committees; Acticor Biotech: Membership on an entity's Board of Directors or advisory committees; Platelet Transcriptomics: Patents & Royalties.
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Stepanov, Alexander, Svetlana A. Usharova, Kristina A. Malsagova, Larisa K. Moshetova, Ksenia I. Turkina, Arthur T. Kopylov, and Anna L. Kaysheva. "Tear Proteome Revealed Association of S100A Family Proteins and Mesothelin with Thrombosis in Elderly Patients with Retinal Vein Occlusion." International Journal of Molecular Sciences 23, no. 23 (November 24, 2022): 14653. http://dx.doi.org/10.3390/ijms232314653.
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Tear samples collected from patients with central retinal vein occlusion (CRVO; n = 28) and healthy volunteers (n = 29) were analyzed using a proteomic label-free absolute quantitative approach. A large proportion (458 proteins with a frequency > 0.6) of tear proteomes was found to be shared between the study groups. Comparative proteomic analysis revealed 29 proteins (p < 0.05) significantly differed between CRVO patients and the control group. Among them, S100A6 (log (2) FC = 1.11, p < 0.001), S100A8 (log (2) FC = 2.45, p < 0.001), S100A9 (log2 (FC) = 2.08, p < 0.001), and mesothelin ((log2 (FC) = 0.82, p < 0.001) were the most abundantly represented upregulated proteins, and β2-microglobulin was the most downregulated protein (log2 (FC) = −2.13, p < 0.001). The selected up- and downregulated proteins were gathered to customize a map of CRVO-related critical protein interactions with quantitative properties. The customized map (FDR < 0.01) revealed inflammation, impairment of retinal hemostasis, and immune response as the main set of processes associated with CRVO ischemic condition. The semantic analysis displayed the prevalence of core biological processes covering dysregulation of mitochondrial organization and utilization of improperly or topologically incorrect folded proteins as a consequence of oxidative stress, and escalating of the ischemic condition caused by the local retinal hemostasis dysregulation. The most significantly different proteins (S100A6, S100A8, S100A9, MSLN, and β2-microglobulin) were applied for the ROC analysis, and their AUC varied from 0.772 to 0.952, suggesting probable association with the CRVO.
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Passey, Robert J., Elizabeth Williams, Agnieszka M. Lichanska, Christine Wells, Shengping Hu, Carolyn L. Geczy, Melissa H. Little, and David A. Hume. "A Null Mutation in the Inflammation-Associated S100 Protein S100A8 Causes Early Resorption of the Mouse Embryo." Journal of Immunology 163, no. 4 (August 15, 1999): 2209–16. http://dx.doi.org/10.4049/jimmunol.163.4.2209.
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Abstract S100A8 (also known as CP10 or MRP8) was the first member of the S100 family of calcium-binding proteins shown to be chemotactic for myeloid cells. The gene is expressed together with its dimerization partner S100A9 during myelopoiesis in the fetal liver and in adult bone marrow as well as in mature granulocytes. In this paper we show that S100A8 mRNA is expressed without S100A9 mRNA between 6.5 and 8.5 days postcoitum within fetal cells infiltrating the deciduum in the vicinity of the ectoplacental cone. Targeted disruption of the S100A8 gene caused rapid and synchronous embryo resorption by day 9.5 of development in 100% of homozygous null embryos. Until this point there was no evidence of developmental delay in S100A8−/− embryos and decidualization was normal. The results of PCR genotyping around 7.5–8.5 days postcoitum suggest that the null embryos are infiltrated with maternal cells before overt signs of resorption. This work is the first evidence for nonredundant function of a member of the S100 gene family and implies a role in prevention of maternal rejection of the implanting embryo. The S100A8 null provides a new model for studying fetal-maternal interactions during implantation.
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McMorran, Brendan J., Severine A. Ouvry Patat, John B. Carlin, Keith Grimwood, Alun Jones, David S. Armstrong, John C. Galati, et al. "Novel Neutrophil-Derived Proteins in Bronchoalveolar Lavage Fluid Indicate an Exaggerated Inflammatory Response in Pediatric Cystic Fibrosis Patients." Clinical Chemistry 53, no. 10 (October 1, 2007): 1782–91. http://dx.doi.org/10.1373/clinchem.2007.087650.
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Abstract Background: Airway inflammation in cystic fibrosis (CF) is exaggerated and characterized by neutrophil-mediated tissue destruction, but its genesis and mechanisms remain poorly understood. To further define the pulmonary inflammatory response, we conducted a proteome-based screen of bronchoalveolar lavage fluid (BALF) collected from young children with and without CF experiencing endobronchial infection. Methods: We collected BALF samples from 45 children younger than 5 years and grouped them according to the presence of respiratory pathogens: ≥1 × 105 colony-forming units (CFU)/mL BALF (18 and 12 samples with and without CF, respectively) and <1 × 105 CFU/mL (23 and 15 samples). BALF proteins were analyzed with SELDI-TOF mass spectrometry (MS) and H4 ProteinChips®. Proteins were identified and characterized using trypsin digestion, tandem MS, Fourier transform ion cyclotron resonance MS, immunoblotting, and ELISA. Results: The SELDI-TOF MS BALF profiles contained 53 unique, reliably detected proteins. Peak intensities of 24 proteins differed significantly between the CF and non-CF samples. They included the neutrophil proteins, α-defensin 1 and 2, S100A8, S100A9, and S100A12, as well as novel forms of S100A8 and S100A12 with equivalent C-terminal deletions. Peak intensities of these neutrophil proteins and immunoreactive concentrations of selected examples were significantly higher in CF than non-CF samples. Conclusions: Small neutrophil-derived BALF proteins, including novel C-terminal truncated forms of S100A proteins, are easily detected with SELDI-TOF MS. Concentrations of these molecules are abnormally high in early CF lung disease. The data provide new insights into CF lung disease and identify novel proteins strongly associated with CF airway inflammation.
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Cooper, Matthew L., Jaebok Choi, Julie Ritchey, and John F. DiPersio. "Dysregulated Overexpression of S100A8 and S100A9 Calgranulin Family Proteins in IFNγR-/- Allogeneic T Cells Is Associated with Reduced Graft Versus Host Disease in Vivo." Blood 124, no. 21 (December 6, 2014): 3828. http://dx.doi.org/10.1182/blood.v124.21.3828.3828.
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Abstract The therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for treatment of hematologic malignancies is primarily derived from the anti-leukemia effect mediated by T cells contained in the donor graft. Unfortunately, these T cells also mediate graft-versus-host disease (GvHD), the major complication of allo-HSCT. We and others have demonstrated that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor grafts, when transplanted into wild-type (WT) recipients (IFNγR-/- donors → WT recipients), reduce GvHD compared with WT donor grafts (WT donors → WT recipients) whilst maintaining a robust Graft vs. Leukemia effect (GvL). The aim of the present study was to elucidate the mechanism by which IFNyR deficient donor T cells reduce GvHD. To achieve this we performed RNA expression analyses on allo-activated T cells. To obtain allo-activated T cells, we co-cultured B6 CD4+CD25- T cells, isolated from WT and IFNγR-/- mice, with irradiated Balb/c antigen presenting cells (APCs). After six days of co-culture, CD4+CD25+ allo-activated T cells were sorted and total RNA extracted. Subsequent RNA profiling was performed using Mouse Genome 430 2.0 array (Affymetrix). From the numerous genes found to be differentially regulated between WT and IFNyR-/- T cells we sought to identify, for further analysis, those genes meeting the following criteria: (i.) genes with known human orthologs, (ii.) genes exhibiting the most pronounced differential expression between WT and IFNγR-/- T cells, (iii.) genes for which knockout or transgenic mice are available and (iv) genes with products that can be targeted by small molecule inhibitors. Two candidates were identified by applying all mentioned criteria: S100A8 and S100A9. Expression levels of S100A8 and S100A9 were 22 and 26 fold higher in APC activated IFNγR-/- T cells than WT T cells, respectively, which was also confirmed using qRT-PCR (Figure 1). It has been reported that S100A8 and S100A9, two members of the calgranulin family of proteins, form a heterodimer complex and may modulate/mitigate several inflammatory diseases by potentially binding NFKB intracellularly and inflammatory cytokines such as IL-6 and TNF when excreted extracellularly.1,2 Overexpression of S100A9 alone is sufficient to upregulate the expression of S100A8 and vice versa.3 In addition, S100A9-/- mice also lack expression of S100A8.4 We hypothesized that S100A8/S100A9 expression in allo-reactive donor T cells functions as a suppressor of GvHD. To test this hypothesis, we performed allo-HSCT with donor T cells isolated from either S100A9 overexpressing transgenic or WT B6 mice transplanted into Balb/c recipients. S100A9 overexpressing donor T cells induced significantly less GvHD than WT T cells. Recipients of S100A9 overexpressing T cells survived significantly longer (p=0.049, n=5), had reduced weight loss and higher percentages of B220+ B cells (indicative of less severe clinical GvHD) than recipients of WT T cells. This suggests that S100A9 might indeed function as a suppressor of GvHD and could account, at least in part, for the diminished GvHD potential of IFNyR-/- T cells. Modulation of the S100A9/A8 complex therefore represents a novel therapeutic target for the treatment of GvHD. Figure 1. The relative expression of S100A8 and S100A9 in allo-activated T Cells determined by qRT-PCR. IFNyR -/- vs. WT APC activated T cells. Figure 1. The relative expression of S100A8 and S100A9 in allo-activated T Cells determined by qRT-PCR. IFNyR -/- vs. WT APC activated T cells. 1. Otsuka K, Terasaki F, Ikemoto M, et al. Suppression of inflammation in rat autoimmune myocarditis by S100A8/A9 through modulation of the proinflammatory cytokine network. Eur J Heart Fail. 2009;11(3):229-237. 2. Ikemoto M, Murayama H, Itoh H, Totani M, Fujita M. Intrinsic function of S100A8/A9 complex as an anti-inflammatory protein in liver injury induced by lipopolysaccharide in rats. Clin Chim Acta. 2007;376(1-2):197-204. 3. Cheng P, Corzo CA, Luetteke N, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008;205(10):2235-2249. 4.Manitz MP, Horst B, Seeliger S, et al. Loss of S100A9 (MRP14) results in reduced interleukin-8-induced CD11b surface expression, a polarized microfilament system, and diminished responsiveness to chemoattractants invitro. Mol Cell Biol. 2003;23(3):1034-1043. Disclosures No relevant conflicts of interest to declare.
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Laouedj, Malika, Mélanie R. Tardif, Laurine Gil, Marie-Astrid Raquil, Asmaa Lachhab, Martin Pelletier, Philippe A. Tessier, and Frédéric Barabé. "S100A9 induces differentiation of acute myeloid leukemia cells through TLR4." Blood 129, no. 14 (April 6, 2017): 1980–90. http://dx.doi.org/10.1182/blood-2016-09-738005.
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Jung, Nicolas, Véronique Schenten, Jean-Luc Bueb, Fabrice Tolle, and Sabrina Bréchard. "miRNAs Regulate Cytokine Secretion Induced by Phosphorylated S100A8/A9 in Neutrophils." International Journal of Molecular Sciences 20, no. 22 (November 14, 2019): 5699. http://dx.doi.org/10.3390/ijms20225699.
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The release of cytokines by neutrophils constitutes an essential process in the development of inflammation by recruiting and activating additional cells. Neutrophils are also able to secrete a complex of S100A8 and S100A9 proteins (S100A8/A9), which can amplify the general inflammatory state of the host and is involved in the pathogenesis of several chronic inflammatory diseases, such as rheumatoid arthritis (RA). S100A8/A9 have received renewed attention due to their susceptibility to several function-altering post-translational modifications. In that context, it has been recently demonstrated that only the phosphorylated form of S100A8/A9 (S100A8/A9-P) is able to induce the secretion of several cytokines in neutrophils. Here, we investigate the mechanism by which this post-translational modification of S100A8/A9 can regulate the extracellular activity of the protein complex and its impact on the inflammatory functions of neutrophils. We found that S100A8/A9-P are present in large amounts in the synovial fluids from RA patients, highlighting the importance of this form of S100A8/A9 complex in the inflammation process. Using miRNA-sequencing on S100A8/A9-P-stimulated differentiated HL-60 cells, we identified a dysregulation of miR-146a-5p and miR-155-5p expression through TRL4 signaling pathways. Our data reveal that overexpression of these miRNAs in neutrophil-like cells reduces S100A8/A9-P-mediated secretion of pro-inflammatory cytokines.
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Zreiqat, Hala, Daniele Belluoccio, Margaret M. Smith, Richard Wilson, Lynn A. Rowley, Katie Jones, Yogambha Ramaswamy, et al. "S100A8 and S100A9 in experimental osteoarthritis." Arthritis Research & Therapy 12, no. 1 (2010): R16. http://dx.doi.org/10.1186/ar2917.
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Roth, J., M. Goebeler, and C. Sorg. "S100A8 and S100A9 in inflammatory diseases." Lancet 357, no. 9261 (March 2001): 1041. http://dx.doi.org/10.1016/s0140-6736(05)71610-x.
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Tomonobu, Nahoko, Rie Kinoshita, Hidenori Wake, Yusuke Inoue, I. Made Winarsa Ruma, Ken Suzawa, Yuma Gohara, et al. "Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells." International Journal of Molecular Sciences 23, no. 18 (September 7, 2022): 10300. http://dx.doi.org/10.3390/ijms231810300.
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The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis.
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Böttcher, Martin, Konstantinos Panagiotidis, Andreas Mackensen, and Dimitrios Mougiakakos. "Stroma Cells Promote a S100A8/A9high-Subset of AML Blasts with Distinct Metabolic Features in a Jak/STAT3-Dependent Manner." Blood 132, Supplement 1 (November 29, 2018): 2807. http://dx.doi.org/10.1182/blood-2018-99-114532.
Full textAbstract:
Abstract Introduction: It is well established that the bone marrow stromal niche can serve as a protective environment in hematological malignancies such as AML by multiple cell contact-dependent and independent mechanisms. Intensive research of the bidirectional interactions between leukemic cells and mesenchymal stromal cells already highlighted numerous modes-of-action how malignant cells are capable of hijacking or altering their surroundings to their own favor. However, the entirety of underlying mechanisms is still incompletely understood. We found two small intracellular calcium-sensing molecules, S100A8 and S100A9, among the top upregulated genes in primary AML cells upon stromal contact. S100A8/A9 are members of the S100 protein family that, by functioning both as intracellular Ca2+ sensors and as extracellular mediators, can modulate cellular responses such as proliferation, migration, inflammation, and differentiation. Dysregulation of S100 protein expression is described as a common feature in several human cancers. Specifically in AML expression of S100A8 in leukemic cells predicts poor survival in de novo AML patients. Thus, we aimed to elucidate the underlying mechanisms of stroma-mediated S100A8/A9 upregulation as well as the consequences, and characterized S100A8/A9high AML cells in comparison to their S100A8/A9low counterparts in terms of gene expression pattern, differentiation, metabolic profiles, and chemoresistance. Methods: We co-cultured both AML cell lines and primary AML blasts in a contact-dependent and -independent manner with human bone marrow stromal cells. After co-culture AML cells were re-purified and analyzed by RNA sequencing, flow cytometry and quantitative real-time PCR. In some experiments, AML cells were sorted based on their S100A8/A9 protein levels and S100A8/A9high cells were compared to S100A8/A9low cells for their transcriptome. Results: We found S100A8 and S100A9 among the top upregulated genes in an unbiased transcriptome analysis of primary AML cells cultured in the presence of HS-5 cells compared tothe controls. Upregulation of S100A8/A9 could be confirmed in AML cell lines and was shown to be reversible. We could demonstrate that S100A8/A9 upregulation is mediated by soluble factors as cell-to-cell contact was not necessary and exosome-free conditioned medium from HS-5 cells did not induce S100A8/A9 gene expression. We found the Jak/STAT3 signaling being one major responsible pathway. The S100A8/A9high population was characterized by increased surface levels of maturation markers (such as CD14 and CD11b) as well as altered metabolically important transporters (e.g. for glucose, fatty and amino acids). Finally, we could demonstrate an increased chemoresistance of the S100A8/A9high cells. Conclusion: We could demonstrate bone marrow stroma-induced S100A8/A9 upregulation in AML cells is mediated by soluble factors activating the Jak/STAT3 pathway. S100A8/A9 leads to metabolic alterations and increased differentiation of AML cells conferring enhanced chemoresistance and thus represents a potential therapeutic target against AML. Disclosures No relevant conflicts of interest to declare.
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Zavorka Thomas, Megan E., Jae Yoon Jeon, Zahra Talebi, Daelynn R. Buelow, Josie Silvaroli, Moray J. Campbell, Alex Sparreboom, Navjot Pabla, and Sharyn D. Baker. "Gilteritinib-induced upregulation of S100A9 is mediated through BCL6 in acute myeloid leukemia." Blood Advances 5, no. 23 (December 3, 2021): 5041–46. http://dx.doi.org/10.1182/bloodadvances.2021005614.
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Abstract Drug resistance and relapse are common challenges in acute myeloid leukemia (AML), particularly in an aggressive subset bearing internal tandem duplications (ITDs) of the FLT3 receptor (FLT3-ITD+). The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet resistance to gilteritinib remains a clinical concern, and the underlying mechanisms remain incompletely understood. Using transcriptomic analyses and functional validation studies, we identified the calcium-binding proteins S100A8 and S100A9 (S100A8/A9) as contributors to gilteritinib resistance in FLT3-ITD+ AML. Exposure of FLT3-ITD+ AML cells to gilteritinib increased S100A8/A9 expression in vivo and in vitro and decreased free calcium levels, and genetic manipulation of S100A9 was associated with altered sensitivity to gilteritinib. Using a transcription factor screen, we identified the transcriptional corepressor BCL6, as a regulator of S100A9 expression and found that gilteritinib decreased BCL6 binding to the S100A9 promoter, thereby increasing S100A9 expression. Furthermore, pharmacological inhibition of BCL6 accelerated the growth rate of gilteritinib-resistant FLT3-ITD+ AML cells, suggesting that S100A9 is a functional target of BCL6. These findings shed light on mechanisms of resistance to gilteritinib through regulation of a target that can be therapeutically exploited to enhance the antileukemic effects of gilteritinib.