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1
Mullins, David W., Ryan S. Martins, and Klaus D. Elgert. "Tumor-Derived Cytokines Dysregulate Macrophage Interferon-γ Responsiveness and Interferon Regulatory Factor-8 Expression." Experimental Biology and Medicine 228, no. 3 (March 2003): 270–77. http://dx.doi.org/10.1177/153537020322800305.
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Tumors can evade immune responses through suppressor signals that dysregulate host effector cell function. In this study we demonstrate that tumor-derived suppressor molecules impede host antitumor immune activity through dysregulation of multiple macrophage (MΦ) pathways, including suppressed production of cytotoxic and immunostimulatory agents and impaired expression of the interferon regulatory factor-8 (IRF-8) protein, a critical transducer of interferon-γ-mediated activation pathways. The tumor-derived immunosuppressive cytokines interieukin-10 and transforming growth factor-β, constrain IRF-8 production by normal MΦs, regardless of priming, and IRF-8 is also dysregulated in primary MΦs from tumorburdened hosts. Collectively, these data describe a new mechanism by which tumors disrupt immune function and suggest that abrogation of tumor-derived immunoregulatory factors in situ can restore immune function and enhance antitumor efficacy.
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De Albuquerque, Nadine, Ehtesham Baig, Xuezhong Ma, Jianhua Zhang, William He, Andrea Rowe, Marlena Habal, et al. "MurineHepatitis Virus Strain 1 Produces a Clinically Relevant Model of Severe Acute Respiratory Syndrome in A/J Mice." Journal of Virology 80, no. 21 (November 1, 2006): 10382–94. http://dx.doi.org/10.1128/jvi.00747-06.
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ABSTRACT Severe acute respiratory syndrome (SARS) is a life-threatening infectious disease which has been difficult to study and treat because of the lack of a readily available animal model. Intranasal infection of A/J mice with the coronavirus murine hepatitis virus strain 1 (MHV-1) produced pulmonary pathological features of SARS. All MHV-1-infected A/J mice developed progressive interstitial pneumonitis, including dense macrophage infiltrates, giant cells, and hyaline membranes, resulting in death of all animals. In contrast, other mouse strains developed only mild transitory disease. Infected A/J mice had significantly higher cytokine levels, particularly macrophage chemoattractant protein 1 (MCP-1/CCL-2), gamma interferon, and tumor necrosis factor alpha. Furthermore, FGL2/fibroleukin mRNA transcripts and protein and fibrin deposits were markedly increased in the lungs of infected A/J mice. These animals developed a less robust type I interferon response to MHV-1 infection than resistant C57BL/6J mice, and treatment with recombinant beta interferon improved survival. This study describes a potentially useful small animal model of human SARS, defines its pathogenesis, and suggests treatment strategies.
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Li, Hao, Lei-Lei Yang, Cong-Cong Wu, Yao Xiao, Liang Mao, Lei Chen, Wen-Feng Zhang, and Zhi-Jun Sun. "Expression and Prognostic Value of IFIT1 and IFITM3 in Head and Neck Squamous Cell Carcinoma." American Journal of Clinical Pathology 153, no. 5 (January 16, 2020): 618–29. http://dx.doi.org/10.1093/ajcp/aqz205.
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Abstract Objectives Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) and interferon-induced transmembrane protein 3 (IFITM3) are commonly induced by type I interferon. The study aims to investigate the expression and clinical significance of IFIT1 and IFITM3 in head and neck squamous cell carcinoma (HNSCC). Methods Immunohistochemistry was applied on tissue microarray to reveal IFIT1 and IFITM3 expression in 275 HNSCC, 69 dysplasia, and 42 normal mucosa samples. The clinicopathologic features associated with IFIT1 and IFITM3 expression in HNSCC patients were analyzed. Results IFIT1 and IFITM3 were highly expressed in HNSCC tissues. High expression of IFIT1 and IFITM3 predicts a negative prognosis for patients (P < .01). IFIT1 and IFITM3 expression was associated with programmed cell death ligand 1, B7-H4, V-domain Ig suppressor of T-cell activation, indoleamine 2,3-dioxygenase, and macrophage marker immunoreactivity. Conclusions IFIT1 and IFITM3 were overexpressed in HNSCC and indicated poor prognoses for patients with HNSCC. IFIT1 and IFITM3 expression was correlated with several immune checkpoint molecules and tumor-associated macrophage markers.
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Kurzrock, R., J. R. Quesada, M. Talpaz, E. M. Hersh, J. M. Reuben, S. A. Sherwin, and J. U. Gutterman. "Phase I study of multiple dose intramuscularly administered recombinant gamma interferon." Journal of Clinical Oncology 4, no. 7 (July 1986): 1101–9. http://dx.doi.org/10.1200/jco.1986.4.7.1101.
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We report the results of a phase I study of the tolerance and biologic activity of intramuscularly (IM)-administered recombinant interferon-gamma (rIFN-gamma). Forty-four patients with metastatic cancer were given rIFN-gamma at doses ranging from 0.01 to 2.5 mg/m2/d for 42 days. The most common side effects were fever, flulike symptoms, night sweats, and granulocytopenia. The maximum tolerated dose was 0.5 mg/m2/d. Administration of rIFN-gamma resulted in modulation of immune system functions, including induction of major histocompatibility complex-associated antigens on blood leukocytes, an increase in blood surface immunoglobulin-bearing B cell and natural killer (NK) cell number, and NK cell cytotoxicity. Serum lysozyme, determined as an estimate of tissue macrophage activity, also increased. Serum assays for anti-interferon antibodies were negative in all patients. Five of eight evaluable patients with lymphoproliferative disorders showed objective evidence of tumor regression consisting of partial responses (two patients), and minor responses (three patients). These data suggest that further phase II studies of IM-administered rIFN-gamma are indicated.
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Arjcharoen, S., C. Wikraiphat, M. Pudla, K. Limposuwan, D. E. Woods, S. Sirisinha, and P. Utaisincharoen. "Fate of a Burkholderia pseudomallei Lipopolysaccharide Mutant in the Mouse Macrophage Cell Line RAW 264.7: Possible Role for the O-Antigenic Polysaccharide Moiety of Lipopolysaccharide in Internalization and Intracellular Survival." Infection and Immunity 75, no. 9 (June 18, 2007): 4298–304. http://dx.doi.org/10.1128/iai.00285-07.
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ABSTRACT Burkholderia pseudomallei is a facultative intracellular gram-negative bacterium that can survive and multiply inside macrophages. One of the mechanisms by which B. pseudomallei escapes macrophage killing is by interfering with the expression of inducible nitric oxide synthase (iNOS). However, the bacterial components that modulate antimicrobial activity of the macrophage have not been fully elucidated. In the present study, we demonstrated that B. pseudomallei strain SRM117, a lipopolysaccharide (LPS) mutant that lacks the O-antigenic polysaccharide moiety, was more susceptible to macrophage killing during the early phase of infection than the parental wild-type strain (1026b). Unlike the wild type, the LPS mutant could readily stimulate Y701-STAT-1 phosphorylation (pY701-STAT-1) and interferon-regulatory factor 1 (IRF-1) expression, both of which are essential transcription factors of iNOS. Neutralizing antibody against beta interferon was able to inhibit the phosphorylation of Y701-STAT-1 and the expression of IRF-1 and iNOS, all of which resulted in an increased rate of intracellular replication. These data suggest that the O-antigenic polysaccharide moiety of B. pseudomallei modulates the host cell response, which in turn controls the intracellular fate of B. pseudomallei inside macrophages.
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Chen, Ruei-Ming, Chih-Hsiung Wu, Huai-Chia Chang, Gong-Jhe Wu, Yi-Ling Lin, Joen-Rong Sheu, and Ta-Liang Chen. "Propofol Suppresses Macrophage Functions and Modulates Mitochondrial Membrane Potential and Cellular Adenosine Triphosphate Synthesis." Anesthesiology 98, no. 5 (May 1, 2003): 1178–85. http://dx.doi.org/10.1097/00000542-200305000-00021.
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Background Propofol is an intravenous anesthetic agent that may impair host defense system. The aim of this study was to evaluate the effects of propofol on macrophage functions and its possible mechanism. Methods Mouse macrophage-like Raw 264.7 cells were exposed to propofol, at 3, 30 (a clinically relevant concentration), and 300 microm. Cell viability, lactate dehydrogenase, and cell cycle were analyzed to determine the cellular toxicity of propofol to macrophages. After administration of propofol, chemotactic, phagocytic, and oxidative ability and interferon-gamma mRNA production were carried out to validate the potential effects of propofol on macrophage functions. Mitochondrial membrane potential and cellular adenosine triphosphate levels were also analyzed to evaluate the role of mitochondria in propofol-induced macrophage dysfunction. Results Exposure of macrophages to 3 and 30 microm propofol did not affect cell viability. When the administered concentration reached 300 microm, propofol would increase lactate dehydrogenase release, cause arrest of cell cycle in G1/S phase, and lead to cell death. In the 1-h-treated macrophages, propofol significantly reduced macrophage functions of chemotactic and oxidative ability in a concentration-dependent manner. However, the suppressive effects were partially or completely reversed after 6 and 24 h. Propofol could reduce phagocytic activities of macrophages in concentration- and time-dependent manners. Exposure of macrophages to lipopolysaccharide induced the mRNA of interferon-gamma, but the induction was significantly blocked by propofol. Propofol concentration-dependently decreased the membrane potential of macrophage mitochondria, but the effects were descended with time. The levels of cellular adenosine triphosphate in macrophages were also reduced by propofol. Conclusions A clinically relevant concentration of propofol can suppress macrophage functions, possibly through inhibiting their mitochondrial membrane potential and adenosine triphosphate synthesis instead of direct cellular toxicity.
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Abe, Chisa, Sachi Tanaka, Fumiaki Ihara, and Yoshifumi Nishikawa. "Macrophage Depletion Prior to Neospora caninum Infection Results in Severe Neosporosis in Mice." Clinical and Vaccine Immunology 21, no. 8 (May 28, 2014): 1185–88. http://dx.doi.org/10.1128/cvi.00082-14.
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ABSTRACTWe observed that murine macrophages showed greater activation and increased interleukin 6 (IL-6), IL-12p40, and interferon gamma (IFN-γ) production duringNeospora caninuminfection. Many macrophages migrated to the site of infection. Furthermore, macrophage-depleted mice exhibited increased sensitivity toN. caninuminfection. This study indicates that macrophages are required for achieving protective immunity againstN. caninum.
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Chen, Xiumei, Yongfeng Lai, Xicheng Song, Jinying Wu, Li Wang, Hua Zhang, Zhonglu Liu, and Yan Wang. "Polysaccharides from Citrus grandis associate with luteolin relieves chronic pharyngitis by anti-inflammatory via suppressing NF-κB pathway and the polarization of M1 macrophages." International Journal of Immunopathology and Pharmacology 32 (January 1, 2018): 205873841878059. http://dx.doi.org/10.1177/2058738418780593.
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Chronic pharyngitis is characterized as a common inflammation of the pharyngeal mucosa, and anti-inflammatory medications are the common treatment to relieve it. Polysacharides of Citrus grandis L. Osbeck (PCG) and luteolin have been reported to have anti-inflammatory activities. In this study, the protective effects of PCG and luteolin on chronic pharyngitis are evaluated and the underlying mechanisms are explored. PCG and luteolin are administrated to animal models with granuloma, ear edema and chronic pharyngitis and the effects of PCG and luteolin on disease severity are evaluated. We also evaluate the effects of PCG and luteolin on inflammatory cytokine production in macrophages stimulated with lipopolysaccharides (LPS)/interferon-gamma (IFN-γ) and detect the effects of PCG and luteolin on macrophage polarization. Finally, we evaluate the effects of PCG and luteolin on activations of LPS-induced downstream signaling pathways. PCG and luteolin alleviate the disease severity of granuloma, ear edema and chronic pharyngitis. PCG and luteolin suppress the productions of pro-inflammatory cytokines interlukin-6 (IL-6), interlukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α) in macrophages. Luteolin promotes macrophage M2 polarization by enhancing expressions of arginase (Arg1) and mannose receptor C type 1 (Mrc1). PCG and luteolin suppress nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and interferon regulatory factor 1 (IRF1), interferon regulatory factor 5 (IRF5) expression. PCG together with luteolin relieves chronic pharyngitis by anti-inflammatory via suppressing NF-κB pathway and the polarization of M1 macrophage.
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Ito, Chihiro, Tomiyasu Murata, Hugh T. W. Tan, Norio Kaneda, Hiroshi Furukawa, and Masataka Itoigawa. "Rotenoid Derivatives from Derris Trifoliata with Nitric Oxide Production Inhibitory Activity." Natural Product Communications 7, no. 11 (November 2012): 1934578X1200701. http://dx.doi.org/10.1177/1934578x1200701117.
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Study of the chemical constituents of the stems of Derris trifoliata Lour. (Leguminosae) collected in Singapore led to the isolation and identification of three known and two new rotenoid derivatives. The new derivatives, named derrisfolin A (1) and B (2), inhibited nitric oxide production in murine macrophage-like RAW 264.7 cells stimulated with interferon-γ and lipopolysaccharide.
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Munder, Markus, Moisés Mallo, Klaus Eichmann, and Manuel Modolell. "Murine Macrophages Secrete Interferon γ upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation." Journal of Experimental Medicine 187, no. 12 (June 15, 1998): 2103–8. http://dx.doi.org/10.1084/jem.187.12.2103.
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Interferon (IFN)-γ, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow– derived macrophages (BMMΦ) secrete large amounts of IFN-γ upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-γ mRNA transcripts, the combined stimulation of BMMΦ with both cytokines leads to the efficient production of IFN-γ protein. The macrophage-derived IFN-γ is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-γ but also a potent IFN-γ–producing cell.
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Ingoglia, Giada, Ayla Yalamanoglu, Marc Pfefferlé, Irina L. Dubach, Christian A. Schaer, Kristyna Valkova, Kerstin Hansen, et al. "Line-selective macrophage activation with an anti-CD40 antibody drives a hemophagocytic syndrome in mice." Blood Advances 4, no. 12 (June 19, 2020): 2751–61. http://dx.doi.org/10.1182/bloodadvances.2020001624.
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Abstract Hemophagocytic syndromes comprise a cluster of hyperinflammatory disorders, including hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Overwhelming macrophage activation has long been considered a final common pathway in the pathophysiology of hemophagocytic syndromes leading to the characteristic cytokine storm, laboratory abnormalities, and organ injuries that define the clinical spectrum of the disease. So far, it is unknown whether primary macrophage activation alone can induce the disease phenotype. In this study, we established a novel mouse model of a hemophagocytic syndrome by treating mice with an agonistic anti-CD40 antibody (Ab). The response in wild-type mice is characterized by a cytokine storm, associated with hyperferritinemia, high soluble CD25, erythrophagocytosis, secondary endothelial activation with multiple organ vaso-occlusion, necrotizing hepatitis, and variable cytopenias. The disease is dependent on a tumor necrosis factor-α–interferon-γ–driven amplification loop. After macrophage depletion with clodronate liposomes or in mice with a macrophage-selective deletion of the CD40 gene (CD40flox/flox/LysMCre), the disease was abolished. These data provide a new preclinical model of a hemophagocytic syndrome and reinforce the key pathophysiological role of macrophages.
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Lai, Yin-Siew, Renanda Baghaz Dzulhamdhani Surya Putra, Shin-Peir Aui, and Ko-Tung Chang. "M2C Polarization by Baicalin Enhances Efferocytosis via Upregulation of MERTK Receptor." American Journal of Chinese Medicine 46, no. 08 (January 2018): 1899–914. http://dx.doi.org/10.1142/s0192415x18500957.
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Baicalin is the main active ingredient primary isolated from the Chinese herb, Scutellaria baicalensis Georgi. Although baicalin can induce M2 macrophage polarization, we still do not know the subtype of macrophages polarized by baicalin. In this study, we characterized that murine bone marrow derived macrophages induced by M-CSF can be further polarized into M2C phenotype by baicalin. The signatures of M2C macrophages for mRNA expression like interferon regulatory factor 4 (IRF4), interleukin-10 (IL-10), MERTK and PTX3 were up-regulated. Moreover, we observed the concomitantly decreasing of tumor necrosis factor alpha (TNF-[Formula: see text]), interferon regulatory factor 5 (IRF5), IL-6. In contrast, M2 macrophages polarized by IL-4 increased gene transcript of arginase-1 (Arg-1) and surface marker of CD206 indicates that their identity as M2A rather than M2C subtypes. Interestingly, the phagocytosis as well as efferocytosis activity were significantly enhanced in M2C macrophage polarized by baicalin and these capacities were associated with the expression of MERTK receptor. Finally, we conclude that baicalin induced M2C macrophages polarization with both elevations of efferocytosis and anti-inflammatory activity.
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Ekchariyawat, P., S. Pudla, K. Limposuwan, S. Arjcharoen, S. Sirisinha, and P. Utaisincharoen. "Burkholderia pseudomallei-Induced Expression of Suppressor of Cytokine Signaling 3 and Cytokine-Inducible Src Homology 2-Containing Protein in Mouse Macrophages: a Possible Mechanism for Suppression of the Response to Gamma Interferon Stimulation." Infection and Immunity 73, no. 11 (November 2005): 7332–39. http://dx.doi.org/10.1128/iai.73.11.7332-7339.2005.
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ABSTRACT Burkholderia pseudomallei, the causative agent of melioidosis, is a facultative intracellular gram-negative bacterium that is able to survive and multiply in macrophages. Previously, we reported that B. pseudomallei was able to escape macrophage killing by interfering with the expression of inducible nitric oxide synthase (iNOS). In the present study, we extended this finding and demonstrated that B. pseudomallei was able to activate the expression of suppressor of cytokine signaling 3 (SOCS3) and cytokine-inducible Src homology 2-containing protein (CIS) but not SOCS1 in a mouse macrophage cell line (RAW 264.7). The expression of SOCS3 and CIS in B. pseudomallei-infected macrophages directly correlated with a decreased gamma interferon (IFN-γ) signaling response, as indicated by a reduction in Y701-STAT-1 phosphorylation (pY701-STAT-1). Moreover, a reduction in the expression of IFN-γ-induced proteins, such as interferon regulatory factor 1 (IRF-1), was observed in B. pseudomallei-infected macrophages that were treated with IFN-γ. Since pY701-STAT-1 and IRF-1 are essential transcription factors for regulating iNOS expression, the failure to activate these factors could also result in depression of iNOS expression and a loss of macrophage killing capacity. Taken together, the data indicate that the activation of SOCS3 and CIS expression in B. pseudomallei-infected macrophages interfered with IFN-γ signaling, thus allowing the bacteria to escape killing by these phagocytic cells.
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GIORGIO, Selma, and Sandra C. BARÃO. "INTRACELLULAR Leishmania amazonensis KILLING INDUCED BY THE GUANINE NUCLEOSIDE 8-BROMOGUANOSINE." Revista do Instituto de Medicina Tropical de São Paulo 40, no. 4 (July 1998): 237–40. http://dx.doi.org/10.1590/s0036-46651998000400006.
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In this study we investigated the effect of 8-Bromoguanosine, an immunostimulatory compound, on the cytotoxicity of macrophages against Leishmania amazonensis in an in vitro system. The results showed that macrophages treated with 8-Bromoguanosine before or after infection are capable to reduce parasite load, as monitored by the number of amastigotes per macrophage and the percentage of infected cells (i.e. phagocytic index). Since 8-Bromoguanosine was not directly toxic to the promastigotes, it was concluded that the ribonucleoside induced macrophage activation. Presumably, 8-Bromoguanosine primed macrophages by inducing interferon alpha and beta which ultimately led to L. amazonensis amastigote killing. The results suggest that guanine ribonucleosides may be useful to treat infections with intracellular pathogens.
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Schlüter, D., M. Deckert, H. Hof, and K. Frei. "Toxoplasma gondii Infection of Neurons Induces Neuronal Cytokine and Chemokine Production, but Gamma Interferon- and Tumor Necrosis Factor-Stimulated Neurons Fail To Inhibit the Invasion and Growth of T. gondii." Infection and Immunity 69, no. 12 (December 1, 2001): 7889–93. http://dx.doi.org/10.1128/iai.69.12.7889-7893.2001.
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ABSTRACT The intracellular parasite Toxoplasma gondii has the capacity to persist in the brain within neurons. In this study we demonstrated that T. gondiiinfected murine cerebellar neurons in vitro and replicated within these cells. Stimulation with gamma interferon (IFN-γ) and/or tumor necrosis factor (TNF) did not enable neurons to inhibit parasite invasion and replication. Cultured neurons constitutively produced interleukin 1 (IL-1), IL-6, macrophage inflammatory protein 1α (MIP-1α), and MIP-1β but not transforming growth factor β1 (TGF-β1), IL-10, and granulocyte-macrophage colony-stimulating factor. Neuronal expression of some cytokines (IL-6, TGF-β1) and chemokines (MIP-1β) was regulated by infection and/or by IFN-γ and TNF.
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Cao, Qian, Junlin Yao, Heyuan Li, Bo Tao, Yibo Cai, Peng Xiao, Hongqiang Cheng, and Yuehai Ke. "Cellular Phenotypic Analysis of Macrophage Activation Unveils Kinetic Responses of Agents Targeting Phosphorylation." SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, no. 1 (September 26, 2016): 51–57. http://dx.doi.org/10.1177/1087057116663166.
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Macrophages are highly plastic cells, which serve as sentinels of the host immune system due to their ability to recognize and respond to microbial products rapidly and dynamically. Appropriate regulation of macrophage activation is essential for pathogen clearance or preventing autoimmune diseases. However, regularly used endpoint assays for analyzing macrophage functions have the limitations of being static and non–high throughput. In this study, we introduced a real-time and convenient method based on changes in cellular impedance that are detected by microelectronic biosensors. This new method can record the time/dose-dependent cell response profiles (TCRPs) of macrophages in real time and generates physiologically relevant data. The TCRPs generated from classically interferon-γ/lipopolysaccharide-activated macrophages showed considerable consistency with the data generated from standard endpoint assays. We further explored this approach by using it for global screening of a library of protein tyrosine kinase/phosphatase (PTK/PTP) inhibitors to investigate their impact on macrophage activation. Collectively, our findings suggest that the cellular impedance-based assay provides a promising approach for dynamically monitoring macrophage functions in a convenient and high-throughput manner.
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Wei, Jia, Daxing Tang, Chengjie Lu, Jin Yang, Yulei Lu, Yidong Wang, Liangliang Jia, et al. "Irf5 deficiency in myeloid cells prevents necrotizing enterocolitis by inhibiting M1 macrophage polarization." Mucosal Immunology 12, no. 4 (May 13, 2019): 888–96. http://dx.doi.org/10.1038/s41385-019-0169-x.
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AbstractNecrotizing enterocolitis (NEC) is a life-threatening inflammatory disease in newborns, but the mechanisms remain unclear. Interferon regulatory factor 5 (IRF5) is a master regulator of macrophage function and is essential for proinflammatory M1 macrophage polarization. Our previous data indicated that M1 macrophages promote NEC injury. Here, we investigated whether IRF5 is involved in the pathogenesis of NEC. First, we found that IRF5 was upregulated in infiltrated macrophages in human neonates with NEC compared to controls. We further confirmed IRF5 upregulation in macrophages in experimental murine NEC and that the infiltrated macrophages were predominantly polarized into the M1 but not the M2 phenotype. Myeloid-specific deficiency of Irf5, which was associated with reduced M1 macrophage polarization and systematic inflammation, dramatically prevented experimental NEC. Moreover, we found that the ablation of Irf5 in myeloid cells markedly suppressed intestinal epithelial cell apoptosis and further prevented intestinal barrier dysfunction in experimental NEC. Bioinformatic and chromatin immunoprecipitation analysis further showed that IRF5 binds to the promoters of the M1 macrophage-associated genes Ccl4, Ccl5, Tnf, and Il12b. Overall, our study provides evidence that IRF5 participates in the pathogenesis of NEC, while the deletion of Irf5 in myeloid cells prevents NEC via inhibiting M1 macrophage polarization.
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Dasgupta, M. K. "Biofilm causes decreased production of interferon-gamma." Journal of the American Society of Nephrology 7, no. 6 (June 1996): 877–82. http://dx.doi.org/10.1681/asn.v76877.
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Interferon-gamma, a cytokine, is produced by lymphocytes when they are stimulated by cytokines from activated macrophages, and is essential for macrophage-mediated bactericidal operations. To investigate whether a strain of bacteria can activate macrophages and lymphocytes, the interferon-gamma levels may thus be measured. Current literature maintains that peritoneal dialysis patients with recurrent peritonitis have "unhealthy" macrophages and lymphocytes unable to produce interferon-gamma, but that the administration of interferon improves the rates of peritonitis. In an in vitro experiment, Staphylococcus epidermidis, in both its planktonic and biofilm forms, was added to a suspension of peritoneal dialysis effluents, macrophages, and healthy peripheral blood lymphocytes, which were incubated at 37 degrees C for 18 h and then centrifuged. Subsequent levels of interferon-gamma were measured in the supernatants. Three such experiments were done with peritoneal macrophages and dialysis effluents collected from each of the three different patients involved in the study. It was found that little or no interferon-gamma (0.42 +/- 0.17 U/mL) was produced when biofilm bacteria were tested, but significant amounts of interferon-gamma (9.25 +/- 4.63 U/mL) resulted in conjunction with the planktonic form of the same bacteria. To eliminate experimental errors, all conditions were left identical, appropriate control groups were added, and each of the three experiments was duplicated. These in vitro data therefore provide new insight in the role of biofilm in the pathogenesis of recurrent peritonitis in peritoneal dialysis patients. Further clinical studies are required.
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Darmani, H., J. L. Harwood, J. Parton, and S. K. Jackson. "Macrophage activation by lipopolysaccharide, interferon-γ and interleukin-4: effect of fatty acid metabolism." Mediators of Inflammation 4, no. 1 (1995): 25–30. http://dx.doi.org/10.1155/s0962935195000056.
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The aim of this study was to investigate the effects of interferon-γ and -β (IFN-γ, -β), interleukin-4 and -10 (IL-4, -10) and Hpopolysaccharide (LPS) on the metabolism and composition of phospholipid fatty acids in macrophages. Murine J774.2 macrophages were incubated with radiolabelled fatty acids and the appropriate stimulus and the incorporation and composition of the phospholipid classes was determined. IFN-γ and IL-4 specifically stimulated enhanced incorporation of [14C]-linoleic acid into the phosphatidytethanolamine fraction. IL-4 (in contrast to IFN-γ and LPS) reduced incorporation of [14C]- arachidonic acid into phosphatidylinositol. Incubation of J774.2 cells with linoleic acid significantly increased TNFα and nitric oxide production; arachidonic acid enhanced TNFα production but reduced nitric oxide production. It is concluded that IFN-γ, IL-4 and IL-10 may differentially regulate macrophage activation via effects on the metabolism of polyunsaturated fatty acids.
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Kotani, Naoki, Hiroshi Hashimoto, Daniel I. Sessler, Hitoshi Yoshida, Naomasa Kimura, Hirobumi Okawa, Masatoshi Muraoka, and Akitomo Matsuki. "Smoking Decreases Alveolar Macrophage Function during Anesthesia and Surgery." Anesthesiology 92, no. 5 (May 1, 2000): 1268–77. http://dx.doi.org/10.1097/00000542-200005000-00014.
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Background Smoking changes numerous alveolar macrophage functions and is one of the most important risk factors for postoperative pulmonary complications. The current study tested the hypothesis that smoking impairs antimicrobial and proinflammatory responses in alveolar macrophages during anesthesia and surgery. Method The authors studied 30 smoking and 30 nonsmoking patients during propofol-fentanyl general anesthesia. Alveolar immune cells were harvested by bronchoalveolar lavage immediately and 2, 4, and 6 h after induction of anesthesia and at the end of surgery. The types of alveolar immune cell and macrophage aggregation were determined. The authors measured opsonized and unopsonized phagocytosis. Microbicidal activity was determined as the ability of the macrophages to kill Listeriamonocytogenes directly. Finally, RNA was extracted from harvested cells and cDNA was synthesized by reverse transcription. The expression of interleukin 1beta, 6, and 8, interferon gamma, and tumor necrosis factor alpha were measured by semiquantitative polymerase chain reaction using beta-actin as an internal standard. Results The fraction of aggregated macrophages increased significantly over time in both groups, whereas phagocytosis of opsonized and nonopsonized particles and microbicidal activity of alveolar macrophages decreased significantly. The changes, though, were nearly twice as great as in patients who smoked. Gene expression of all proinflammatory cytokines in alveolar immune cells except interleukin 6 increased 2- to 20-fold over time in both groups. The expression of interleukin 1beta, interferon gamma, and tumor necrosis factor alpha, however, increased only half as much in smokers as in nonsmokers. Conclusion Smoking was associated with macrophage aggregation but markedly reduced phagocytic and microbicidal activity-possibly because expression of proinflammatory cytokines was reduced in these patients. Our data thus suggest that smokers may have a limited ability to mount an effective pulmonary immune defense after anesthesia and surgery.
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Jeevan, A., C. T. McFarland, T. Yoshimura, T. Skwor, H. Cho, T. Lasco, and D. N. McMurray. "Production and Characterization of Guinea Pig Recombinant Gamma Interferon and Its Effect on Macrophage Activation." Infection and Immunity 74, no. 1 (January 2006): 213–24. http://dx.doi.org/10.1128/iai.74.1.213-224.2006.
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ABSTRACT Gamma interferon (IFN-γ) plays a critical role in the protective immune responses against mycobacteria. We previously cloned a cDNA coding for guinea pig IFN-γ (gpIFN-γ) and reported that BCG vaccination induced a significant increase in the IFN-γ mRNA expression in guinea pig cells in response to living mycobacteria and that the virulent H37Rv strain of Mycobacterium tuberculosis stimulated less IFN-γ mRNA than did the attenuated H37Ra strain. In this study, we successfully expressed and characterized recombinant gpIFN-γ with a histidine tag at the N terminus (His-tagged rgpIFN-γ) in Escherichia coli. rgpIFN-γ was identified as an 18-kDa band in the insoluble fraction; therefore, the protein was purified under denaturing conditions and renatured. N-terminal amino acid sequencing of the recombinant protein yielded the sequence corresponding to the N terminus of His-tagged gpIFN-γ. The recombinant protein upregulated major histocompatibility complex class II expression in peritoneal macrophages. The antiviral activity of rgpIFN-γ was demonstrated with a guinea pig fibroblast cell line (104C1) infected with encephalomyocarditis virus. Interestingly, peritoneal macrophages treated with rgpIFN-γ did not produce any nitric oxide but did produce hydrogen peroxide and suppressed the intracellular growth of mycobacteria. Furthermore, rgpIFN-γ induced morphological alterations in cultured macrophages. Thus, biologically active rgpIFN-γ has been successfully produced and characterized in our laboratory. The study of rgpIFN-γ will further increase our understanding of the cellular and molecular responses induced by BCG vaccination in the guinea pig model of pulmonary tuberculosis.
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Machado, Patrícia de Almeida, Douglas Oliveira Escrivani, Daniel Claudio Oliveira Gomes, Bartira Rossi-Bergmann, Suzana Passos Chaves, Elaine Soares Coimbra, and Herbert Leonel de Matos Guedes. "Vitamin D increases killing of intracellular Leishmania amazonensis in vitro independently of macrophage oxidative mechanisms." Parasitology 147, no. 14 (September 22, 2020): 1792–800. http://dx.doi.org/10.1017/s0031182020001791.
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AbstractVitamin D has been reported to activate macrophage microbicidal mechanisms by inducing the production of antimicrobial peptides and nitric oxide (NO), but conversely has been shown to contribute to a greater susceptibility to Leishmania amazonensis infection in mice. Thus, this study aimed to evaluate the role of vitamin D during intracellular infection with L. amazonensis by examining its effect on macrophage oxidative mechanisms and parasite survival in vitro. Vitamins D2 and D3 significantly inhibited promastigote and amastigote growth in vitro. Vitamin D3 was not able to induce NO and reactive oxygen species (ROS) production in uninfected macrophages or macrophages infected with L. amazonensis. In addition, vitamin D3 in combination with interferon (IFN)-γ did not enhance amastigote killing and in fact, significantly reduced NO and ROS production when compared with the effect of IFN-γ alone. In this study, we demonstrated that vitamin D directly reduces parasite growth in infected macrophages (approximately 50–60% at 50 μm) but this effect is independent of the activation of macrophage oxidative mechanisms. These findings will contribute to a better understanding of the role of vitamin D in cutaneous leishmaniasis.
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Thein, Mya Sanda, Alka Jain, Maria Clara Ingaramo, Antia Kohli, and Neal Fedarko. "Role of chronic macrophage activation in patients with primary breast cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13042-e13042. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13042.
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e13042 Background: Breast cancer progression has been associated with altered immune function and macrophage activation. Neopterin (Neo), a GTP metabolite, is secreted by interferon-γ activated macrophages. Chitotriosidase (ChT), a member of the glycosyl hydrolase family, is secreted by chronically activated macrophages. Osteopontin (OPN), a phosphorylated glycoprotein, produced by tumor and immune cells, is a modulator of macrophage activity and infiltration. OPN and neopterin have been studied separately as markers of solid malignancy including breast cancer. Methods: The purpose of our study was to test for correlations between breast cancer presence and stage with macrophage produced markers of acute (Neo), and chronic (ChT) macrophage activation as well as tumor/immune cell produced marker of macrophage infiltration (OPN). The study included 66 patients with primary breast cancer (Group I: 14 with metastatic disease) and 111 participants in a control group (Group II). Serum levels of OPN and Neo were measured by ELISA, while ChT levels in serum were measured by enzyme activity assays. Comparisons between groups were analyzed by Mann Whitney U test. Results: ChT and OPN levels were significantly higher in Group I compared to Group II (Table I). ChT was elevated at early stage disease while OPN increased with more advanced disease. Although Neo was not increased in patients with breast cancer, a subgroup analysis within group I demonstrated that it was higher in patients with metastatic disease (6.8 vs 9.3 p <0.01). Conclusions: High levels of ChT in breast cancer patients may indicate that chronic macrophage activation plays a significant role in early breast cancer progression. OPN and Neo, elevated in late stage and metastatic disease, respectively may be useful biomarkers of tumor aggressiveness and/or metastatic progression. Further studies should be done to validate these biomarkers and understand the role of acute and chronic macrophage activation in cancer progression. [Table: see text]
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Cheung, DL, and JA Hamilton. "Regulation of human monocyte DNA synthesis by colony-stimulating factors, cytokines, and cyclic adenosine monophosphate." Blood 79, no. 8 (April 15, 1992): 1972–81. http://dx.doi.org/10.1182/blood.v79.8.1972.1972.
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Abstract It is reported in this study that a subpopulation of highly purified human peripheral blood human monocytes can proliferate in response to colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony- stimulating factor (GM-CSF), and interleukin-3 (IL-3). Both GM-CSF and IL-3 synergized with CSF-1 for the induction of DNA synthesis. Given the DNA synthesis levels attained, we were able to test the effects of certain cytokines and cyclic adenosine monophosphate (cAMP)-elevating agents, which have been shown to modulate in vitro human myelopoiesis and murine macrophage proliferation. The cytokines, interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF- alpha), as well as cAMP-elevating agents, 8-bromoadenosine 3′:5′-cyclic monophosphate (8BrcAMP), cholera toxin (CT), and prostaglandin E2 (PGE2), suppressed the monocyte DNA synthesis due to CSF-1. These results parallel those reported with human bone marrow progenitors, as well as murine macrophage populations. The cycling human monocyte population could provide a model cell type to understand the molecular events controlling human myelopoiesis.
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Cheung, DL, and JA Hamilton. "Regulation of human monocyte DNA synthesis by colony-stimulating factors, cytokines, and cyclic adenosine monophosphate." Blood 79, no. 8 (April 15, 1992): 1972–81. http://dx.doi.org/10.1182/blood.v79.8.1972.bloodjournal7981972.
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It is reported in this study that a subpopulation of highly purified human peripheral blood human monocytes can proliferate in response to colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony- stimulating factor (GM-CSF), and interleukin-3 (IL-3). Both GM-CSF and IL-3 synergized with CSF-1 for the induction of DNA synthesis. Given the DNA synthesis levels attained, we were able to test the effects of certain cytokines and cyclic adenosine monophosphate (cAMP)-elevating agents, which have been shown to modulate in vitro human myelopoiesis and murine macrophage proliferation. The cytokines, interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF- alpha), as well as cAMP-elevating agents, 8-bromoadenosine 3′:5′-cyclic monophosphate (8BrcAMP), cholera toxin (CT), and prostaglandin E2 (PGE2), suppressed the monocyte DNA synthesis due to CSF-1. These results parallel those reported with human bone marrow progenitors, as well as murine macrophage populations. The cycling human monocyte population could provide a model cell type to understand the molecular events controlling human myelopoiesis.
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Harris, Bethany D., Srilalitha Kuruganti, Ashlesha Deshpande, Paul A. Goepfert, W. Winn Chatham, and Mark R. Walter. "Characterization of Type-I IFN subtype autoantibodies and activity in SLE serum and urine." Lupus 29, no. 9 (July 1, 2020): 1095–105. http://dx.doi.org/10.1177/0961203320935976.
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Background/objective Type-I interferons contribute to pathogenesis in systemic lupus erythematosus, including nephritis. Interferons consist of a family of 16 proteins yet are often characterized in patients without knowledge of the specific interferon subtypes involved. Different interferons may function in the kidneys, and other organs, relative to what is often measured in patient blood. Moreover, antibodies to interferons may potentially modulate systemic or organ-specific interferon activity. The aim of this study was to characterize global interferon activity levels and identify autoantibodies to the 12 interferon α subtypes in patient serum and urine. Methods Interferon activity levels in serum and urine were measured using an interferon bioassay. Anti-interferon and anti-cytokine autoantibodies were measured by ELISA. Serum and urine samples were also characterized for their ability to neutralize the biological activity of exogenously added interferons. Results Serum interferon activity was increased in 62% of systemic lupus erythematosus patient samples, relative to healthy donor controls, whereas binding interferon α autoantibodies to at least one interferon α subtype were found in 68% of the samples evaluated. High Systemic Lupus Erythematosus Disease Activity Index scores were significantly ( p = 0.001) associated with patient samples containing interferon α autoantibodies to three or more interferon α subtypes in their serum. Interferon α autoantibodies that potently block interferon activity were rare (∼5% of samples), but collectively bound to all 12 interferon α subtypes. Urine interferon activity and interferon α autoantibody profiles did not correlate with their serum counterparts, suggesting immune responses in systemic lupus erythematosus kidneys can be distinct from those measured in serum. Analysis of autoantibodies to 15 additional cytokines in serum identified higher frequencies of granulocyte-macrophage colony-stimulating factor and interleukin 17A autoantibodies, suggesting these signaling pathways may potentially contribute, with interferons, to systemic lupus erythematosus pathogenesis. Conclusions The measurement of autoantibodies to multiple interferon subtypes in serum and urine may provide an alternative method for following interferon-mediated systemic lupus erythematosus disease activity. The results suggest autoantibodies might be used for patient monitoring and/or identifying additional cytokine signaling pathways that are functioning in different systemic lupus erythematosus patients.
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Filipič, Bratko, Klemen Rihar, Dunja Exel Gregorič, Lidija Gradišnik, Adriana Pereyra, Damir Đermić, Časlav Daničić, and Hrvoje Mazija. "Enhancing Effect of 100.414-kHz Electromagnetic Field Produced by Defender’s Pulse Generator on the ChIFN γ-Like Molecule Inducing Capacity of Lens culinaris Agglutinin and 10% PBS Washouts of Different Holocene Minerals." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381882109. http://dx.doi.org/10.1177/1533033818821093.
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Macrophages play key role in host defense and tissue repair, and thus understanding regulation of their function is important. For instance, our previous results have shown that in chicken macrophage system (CoMA cell line), application of a pulse of electromagnetic fields of frequencies 0.618, 1.054, 5.229, and 100.414 kHz induces production of interferon γ-like molecules. In this study, we have shown that the electromagnetic field of 100.414 kHz is the most effective in inducing synthesis of chicken interferon γ and chicken interferon γ-like molecules in CoMA cells, especially when combined with Lens culinaris agglutinin and 10% phosphate-buffered saline washouts of different Holocene minerals. A 2-minute pulse of electromagnetic field was produced by Defender’s pulse generator. Both chicken interferon γ and chicken interferon γ-like molecules from the cell supernatant were evaluated by an antiviral assay and were also analyzed with reverse-phase high-performance liquid chromatography on Phenomenex, Aeris peptide columns. Our results show that application of a single inducing factor ( Lens culinaris agglutinin, 100.414 kHz electromagnetic field, 10% phosphate buffer saline washout) or combined usage of 2 of them moderately stimulated production of chicken interferon γ-like molecules (from 1.550 to 48.028 IU/mL), whereas the combination of 10% phosphate-buffered saline washout of Koprivnica rock + Lens culinaris agglutinin + 100.414 kHz/9 V resulted in an output of 162.122 IU/mL. Hence, we may conclude that a combined use of electromagnetic field, Holocene minerals, and Lens culinaris agglutinin greatly stimulates synthesis of chicken interferon γ-like molecules in CoMA cells.
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Reinisch, Walter, Margareta Holub, Andreas Katz, Andreas Herneth, Cornelia Lichtenberger, Maximilian Schoniger-Hekele, Thomas Waldhoer, et al. "Prospective Pilot Study of Recombinant Granulocyte-Macrophage Colony-Stimulating Factor and Interferon-γ in Patients With Inoperable Hepatocellular Carcinoma." Journal of Immunotherapy 25, no. 6 (November 2002): 489–99. http://dx.doi.org/10.1097/00002371-200211000-00005.
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Hogan, Vanessa E., Cécile T. J. Holweg, David F. Choy, Sarah K. Kummerfeld, Jason A. Hackney, Y. K. Onno Teng, Michael J. Townsend, and Jacob M. vanLaar. "Pretreatment synovial transcriptional profile is associated with early and late clinical response in rheumatoid arthritis patients treated with rituximab." Annals of the Rheumatic Diseases 71, no. 11 (June 26, 2012): 1888–94. http://dx.doi.org/10.1136/annrheumdis-2011-201115.
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ObjectivePersonalised healthcare is contingent on the identification of biomarkers that represent disease relevant pathways and predict drug response. The authors aimed to develop a gene expression signature in synovial tissue that could enrich clinical response of rheumatoid arthritis (RA) patients to rituximab.MethodsThe authors studied synovial gene expression using high-throughput quantitative real-time-PCR in 20 RA patients who underwent arthroscopy before and after treatment with rituximab. Several objective approaches were used to explore patterns in the data and to find genes associated with changes in disease activity due to treatment.ResultsThis analysis revealed two patient populations associated with distinct clinical, laboratory and histological features and, importantly, showed enrichment for response (60% non-responders vs 90% responders). A composite baseline gene score (GS) correlated with change in disease activity score (ΔDAS) between baseline and month 3 (r=0.74, p=0.0002), but also with ΔDAS at later time-points (month 9, r=0.54, p=0.016; month 15, r=0.45, p=0.06; month 21, r=0.72, p=0.003). Notably, the GS significantly correlated with baseline erythrocyte sedimentation rate (r=0.69, p=0.0008), but not with other DAS components. The GS genes represented T cell, macrophage, remodelling and interferon-α biology. Responders demonstrated higher expression of macrophage and T cell genes, while non-responders showed higher expression of interferon-α and remodelling genes.ConclusionsThis study reveals a baseline synovial GS that correlates with early and late clinical responses to rituximab. The GS biology suggests that T cells and macrophages are important for response to B cell depleting therapy, while expression of remodelling and interferon-α genes correlates with poor response.
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Kostik, M., R. Raupov, R. Mulkidzhan, A. Kosmin, and E. Suspitsin. "AB0001 INTERFERON SIGNATURE IN CHILDREN WITH CHRONIC NON-BACTERIAL OSTEOMYELITIS AND IT’S DYNAMIC AFTER BISPHOSPHONATES TREATMENT." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1036.2–1036. http://dx.doi.org/10.1136/annrheumdis-2021-eular.508.
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Background:Chronic non-bacterial osteomyelitis (CNO) is an immune-mediated chronic inflammatory bone disease which predominantly affects children and adolescents. The pathogenesis of CNO related to imbalance between pro-inflammatory and anti-inflammatory cytokines. Interferon-I mediated pathway is associated with pathogenesis of different pediatric rheumatic diseases, such as juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), systemic onset of juvenile idiopathic arthritis (soJIA), and, most of all, with macrophage activation syndrome. The data on interferon-I- regulated pathway in CNO is absent. NSAIDs, non-biologic and biologic anti-inflammatory drugs and bisphosphonates (BF) are treatment options for patients with CNO. The main adverse event of BF is a flu-like syndrome probably caused by the excessive cytokine release stimulated by BF.Objectives:The aim of our study was to evaluate activity of Interferon-I mediated pathway in CNO patients and it’s dynamics after BF treatment.Methods:This prospective study included children with CNO requiring BF treatment (n=9), patients with soJIA (n=8), JDM (n=11) and jSLE (n=40) and healthy controls (HC, n=21). The activity of Interferon-I mediated pathway was assessed using interferon I score (IFN1 score). The score represented the median expression of 5 IFN1-regulated genes (IFI44L, IFI44, IFIT3, LY6E, MX1) measured by quantitative real-time PCR. Patients with CNO were treated with standard 3-day regimen (1 mg/kg/day). We measured interferon score before pamidronate (Day 0, n=9) and after (Day 3, n=7).Results:Median interferon score was 1.09 (0.96; 1.67) in CNO patients, 1.95 (1.3; 5.75) in soJIA, 7.6 (1.78; 29.0) in JDM and 16.9 (2.55; 40.3) in jSLE and 0.95 (0.82; 1.17) in HC (p=0.00001). Where were no difference in the IFN1 score between CNO and HC (p=0.222). In 6/7 CNO patients interferon score increased after pamidronate (p=0.015). The median interferon score after pamidronate increased and became 3.06 (0.87; 4,9, p=0.043); this may possibly explain the development of BF-related flu-like symptoms (cytokine release syndrome).Conclusion:While interferon I-regulated pathway is not directly associated with CNO pathogenesis, BF likely activates interferon-I-regulated pathway and thus could be a possible cause of flu-like syndrome.This work supported by the Russian Foundation for Basic Research (grant № 18-515-57001).Disclosure of Interests:None declared
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Zhang, Xiaoxia, and Yen-Tung A. Teng. "Interleukin-10 Inhibits Gram-Negative-Microbe-Specific Human Receptor Activator of NF-κB Ligand-Positive CD4+-Th1-Cell- Associated Alveolar Bone Loss In Vivo." Infection and Immunity 74, no. 8 (August 2006): 4927–31. http://dx.doi.org/10.1128/iai.00491-06.
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ABSTRACT To study anti-inflammatory cytokine effects on RANKL+-T-cell-mediated osteoclastogenesis in vivo, we injected human interleukin-10 (hIL-10) into pathogen-infected HuPBL-NOD/SCID mice. The results show significantly decreased RANKL+ Th1-associated alveolar bone loss and coexpression of human gamma interferon (hIFN-γ) and human macrophage colony-stimulating factor, but not hIL-4, in RANKL+ Th cells compatible with those from successfully treated aggressive periodontitis subjects. Thus, there are critical cytokine interactions linking hIFN-γ+ Th1 cells to RANKL-RANK/OPG signaling for periodontal osteoclastogenesis in vivo.
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Kohut, M. L., J. M. Davis, D. A. Jackson, P. Jani, A. Ghaffar, E. P. Mayer, and D. A. Essig. "Exercise effects on IFN-β expression and viral replication in lung macrophages after HSV-1 infection." American Journal of Physiology-Lung Cellular and Molecular Physiology 275, no. 6 (December 1, 1998): L1089—L1094. http://dx.doi.org/10.1152/ajplung.1998.275.6.l1089.
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Mice exercised to fatigue and exposed to herpes simplex virus type 1 (HSV-1) exhibit greater mortality than control mice. In this study, we examined lung macrophage resistance to HSV-1 after exercise in terms of both viral replication and interferon (IFN)-β production. We utilized the reverse transcriptase-rapid polymerase chain reaction to measure the IFN-β mRNA content in alveolar macrophages. IFN release was measured with a bioassay, and viral replication within the macrophage was assessed by plaque titration. Exercised (Ex) mice ran on a treadmill until fatigue while control (Con) mice remained in lanes above the treadmill. After exercise, alveolar macrophages were removed and incubated with HSV-1. Alveolar macrophage IFN-β mRNA was greater in Ex than in Con mice. Culture supernatant from infected macrophages showed a higher degree of IFN release and a higher number of infectious viral particles in Ex vs. Con mice. It is likely that the increase in IFN-β mRNA occurs in response to a higher degree of viral replication. These results suggest that macrophages from Ex mice are less resistant to infection with HSV-1.
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Pudla, M., K. Limposuwan, and P. Utaisincharoen. "Burkholderia pseudomallei-Induced Expression of a Negative Regulator, Sterile-α and Armadillo Motif-Containing Protein, in Mouse Macrophages: a Possible Mechanism for Suppression of the MyD88-Independent Pathway." Infection and Immunity 79, no. 7 (May 9, 2011): 2921–27. http://dx.doi.org/10.1128/iai.01254-10.
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ABSTRACTBurkholderia pseudomallei, a causative agent of melioidosis, is a Gram-negative facultative intracellular bacterium that can survive and multiply in macrophages. Previously, we demonstrated thatB. pseudomalleifailed to activate gene expression downstream of the MyD88-independent pathway, particularly the expression of beta interferon (IFN-β) and inducible nitric oxide synthase (iNOS), leading to the inability of macrophages to kill this bacterium. In the present report, we extended our study to show thatB. pseudomalleiwas able to activate sterile-α and Armadillo motif (SARM)-containing protein, a known negative regulator of the MyD88-independent pathway. Both liveB. pseudomalleiand heat-killedB. pseudomalleiwere able to upregulate SARM expression in a time-dependent manner in mouse macrophage cell line RAW 264.7. The expression of SARM required bacterial internalization, as it could be inhibited by cytochalasin D. In addition, the intracellular survival ofB. pseudomalleiwas suppressed in SARM-deficient macrophages. Increased expression of IFN-β and iNOS and degradation of IκBα correlated with enhanced macrophage killing capability. These results demonstrated thatB. pseudomalleimodulated macrophage defense mechanisms by upregulating SARM, thus leading to the suppression of IFN-β and iNOS needed for bacterial elimination.
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Gries, Casey M., Eric L. Bruger, Derek E. Moormeier, Tyler D. Scherr, Christopher M. Waters, and Tammy Kielian. "Cyclic di-AMP Released from Staphylococcus aureus Biofilm Induces a Macrophage Type I Interferon Response." Infection and Immunity 84, no. 12 (October 10, 2016): 3564–74. http://dx.doi.org/10.1128/iai.00447-16.
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Staphylococcus aureus is a leading cause of community- and nosocomial-acquired infections, with a propensity for biofilm formation. S. aureus biofilms actively skew the host immune response toward an anti-inflammatory state; however, the biofilm effector molecules and the mechanism(s) of action responsible for this phenomenon remain to be fully defined. The essential bacterial second messenger cyclic diadenylate monophosphate (c-di-AMP) is an emerging pathogen-associated molecular pattern during intracellular bacterial infections, as c-di-AMP secretion into the infected host cytosol induces a robust type I interferon (IFN) response. Type I IFNs have the potential to exacerbate infectious outcomes by promoting anti-inflammatory effects; however, the type I IFN response to S. aureus biofilms is unknown. Additionally, while several intracellular proteins function as c-di-AMP receptors in S. aureus , it has yet to be determined if any extracellular role for c-di-AMP exists and its release during biofilm formation has not yet been demonstrated. This study examined the possibility that c-di-AMP released during S. aureus biofilm growth polarizes macrophages toward an anti-inflammatory phenotype via type I interferon signaling. DacA, the enzyme responsible for c-di-AMP synthesis in S. aureus , was highly expressed during biofilm growth, and 30 to 50% of total c-di-AMP produced from S. aureus biofilm was released extracellularly due to autolytic activity. S. aureus biofilm c-di-AMP release induced macrophage type I IFN expression via a STING-dependent pathway and promoted S. aureus intracellular survival in macrophages. These findings identify c-di-AMP as another mechanism for how S. aureus biofilms promote macrophage anti-inflammatory activity, which likely contributes to biofilm persistence.
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Tesch, G. H., D. J. Nikolic-Paterson, C. N. Metz, W. Mu, M. Bacher, R. Bucala, R. C. Atkins, and H. Y. Lan. "Rat mesangial cells express macrophage migration inhibitory factor in vitro and in vivo." Journal of the American Society of Nephrology 9, no. 3 (March 1998): 417–24. http://dx.doi.org/10.1681/asn.v93417.
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Mesangial cells are thought to promote glomerular macrophage accumulation in glomerulonephritis. This may occur through the production of macrophage migration inhibitory factor (MIF), a molecule known to regulate macrophage accumulation at sites of inflammation. To study this, glomerular MIF expression and macrophage accumulation were examined in rat anti-Thy-1 disease, a model of mesangioproliferative nephritis. In situ hybridization and immunohistochemistry showed that MIF is expressed by some podocytes in normal rat glomeruli. De novo MIF expression by glomerular endothelium was seen on day 1 of anti-Thy-1 disease. On day 6, glomerular MIF mRNA and protein expression were prominent in segmental proliferative lesions, which was also the location of most infiltrating macrophages. Double-staining identified de novo MIF mRNA and protein expression by proliferating mesangial cells within these lesions. Cytokine regulation of mesangial cell MIF expression was examined in vitro. Northern blotting showed that cultured rat mesangial cells express a single 0.6-kb species of MIF mRNA, and Western blotting detected a single protein band of 12.5 kD. Six-hour stimulation of mesangial cells with interferon-gamma or platelet-derived growth factor significantly increased MIF mRNA levels. However, the addition of recombinant MIF to mesangial cells did not affect mesangial cell proliferation or constitutive transforming growth factor-beta mRNA expression, nor did MIF induce monocyte chemoattractant protein-1 mRNA expression. In conclusion, this is the first study to demonstrate that mesangial cells can produce MIF in vivo and in vitro. It is postulated that mesangial cell MIF production in response to injury acts to promote macrophage accumulation within segmental proliferative lesions in rat anti-Thy-1 nephritis.
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Lei, D., J. R. Lancaster, M. S. Joshi, S. Nelson, D. Stoltz, G. J. Bagby, G. Odom, J. E. Shellito, and J. K. Kolls. "Activation of alveolar macrophages and lung host defenses using transfer of the interferon-gamma gene." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 5 (May 1, 1997): L852—L859. http://dx.doi.org/10.1152/ajplung.1997.272.5.l852.
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Interferon-gamma (IFN-gamma) is a critical cytokine in pulmonary host defenses against both intracellular and extracellular pathogens. To investigate whether this cytokine could be used therapeutically, we constructed an E1-deleted recombinant adenovirus encoding murine IFN-gamma. After intratracheal inoculation in rats, this vector resulted in prolonged expression of functional cytokine in vivo, as demonstrated by increased alveolar macrophage class II major histocompatibility complex expression, enhanced release of tumor necrosis factor in response to lipopolysaccharide, and enhanced host defenses against Pseudomonas aeruginosa. We postulate that this vector may be useful to study the role of exogenous IFN-gamma in a variety of pulmonary intracellular and extracellular pathogens.
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Cassano, Paolo, Eric Bui, Andrew H. Rogers, Zandra E. Walton, Rachel Ross, Mary Zeng, Mireya Nadal-Vicens, et al. "Inflammatory cytokines in major depressive disorder: A case–control study." Australian & New Zealand Journal of Psychiatry 51, no. 1 (September 29, 2016): 23–31. http://dx.doi.org/10.1177/0004867416652736.
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Introduction: There is mixed evidence in the literature on the role of inflammation in major depressive disorder. Contradictory findings are attributed to lack of rigorous characterization of study subjects, to the presence of concomitant medical illnesses, to the small sample sizes, and to the limited number of cytokines tested. Methods: Subjects aged 18–70 years, diagnosed with major depressive disorder and presenting with chronic course of illness, as well as matched controls ( n = 236), were evaluated by trained raters and provided blood for cytokine measurements. Cytokine levels in EDTA plasma were measured with the MILLIPLEX Multi-Analyte Profiling Human Cytokine/Chemokine Assay employing Luminex technology. The Wilcoxon rank-sum test was used to compare cytokine levels between major depressive disorder subjects and healthy volunteers, before (interleukin [IL]-1β, IL-6, and tumor necrosis factor-α) and after Bonferroni correction for multiple comparisons (IL-1α, IL-2, IL-3, IL-4, IL-5, IL-7, IL-8, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IFN-γ-inducible protein 10, Eotaxin, interferon-γ, monotype chemoattractant protein-1, macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor and vascular endothelial growth factor). Results: There were no significant differences in cytokine levels between major depressive disorder subjects and controls, both prior to and after correction for multiple analyses (significance set at p ⩽ 0.05 and p ⩽ 0.002, respectively). Conclusion: Our well-characterized examination of cytokine plasma levels did not support the association of major depressive disorder with systemic inflammation. The heterogeneity of major depressive disorder, as well as a potential sampling bias selecting for non-inflammatory depression, might have determined our findings discordant with the literature.
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Rocha, Magda F. G., Alexandra A. P. Mansur, Camila P. S. Martins, Edel F. Barbosa-Stancioli, and Herman S. Mansur. "Macrophage Response to UHMWPE Submitted to Accelerated Ageing in Hydrogen Peroxide." Open Biomedical Engineering Journal 4, no. 1 (June 10, 2010): 107–12. http://dx.doi.org/10.2174/1874120701004010107.
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Ultra-high molecular weight polyethylene (UHMWPE) has been the most commonly used bearing material in total joint arthroplasty. Wear and oxidation fatigue resistance of UHMWPE are regarded as two important properties to extend the longevity of knee prostheses. The present study investigated the accelerated ageing of UHMWPE in hydrogen peroxide highly oxidative chemical environment. The sliced samples of UHMWPE were oxidized in a hydrogen peroxide solution for 120 days with their total level of oxidation (Iox) characterized by Fourier Transformed Infrared Spectroscopy (FTIR). The potential inflammatory response, cell viability and biocompatibility of such oxidized UHMWPE systems were assessed by a novel biological in vitro assay based on the secretion of nitric oxide (NO) by activated murine macrophages with gamma interferon (IFN-γ) cytokine and lipopolysaccharide (LPS). Furthermore, macrophage morphologies in contact with UHMWPE oxidized surfaces were analyzed by cell spreading-adhesion procedure using scanning electron microscopy (SEM). The results have given significant evidence that the longer the period of accelerated aging of UHMWPE the higher was the macrophage inflammatory equivalent response based on NO secretion analysis.
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Wang, Xin-An, Ran Zhang, Shumin Zhang, Shan Deng, Dingsheng Jiang, Jinfeng Zhong, Li Yang, et al. "Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance." American Journal of Physiology-Endocrinology and Metabolism 305, no. 4 (August 15, 2013): E485—E495. http://dx.doi.org/10.1152/ajpendo.00505.2012.
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Obesity-related inflammation has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. In this study, we addressed the potential role of interferon regulatory factor 7 (IRF7), a master regulator of type I interferon-dependent immune responses, in the regulation of energy metabolism. The expression levels of IRF7 were increased in white adipose tissue, liver tissue, and gastrocnemius muscle of both diet-induced obese mice and ob/ ob mice compared with their lean counterparts. After feeding a high-fat diet (HFD) for 24 wk, IRF7 knockout (KO) mice showed less weight gain and adiposity than wild-type controls. KO of IRF7 improved glucose and lipid homeostasis and insulin sensitivity. Additionally, KO of IRF7 ameliorated diet-induced hepatic steatosis. Next, we assessed the inflammatory state of the IRF7 KO mice on the HFD. These mice showed less macrophage infiltration into multiple organs and were protected from local and systemic inflammation. This study demonstrates a role for IRF7 in diet-induced alterations in energy metabolism and insulin sensitivity. Our results also suggest that IRF7 is involved in the etiology of metabolic abnormalities, which suggests a new strategy for treating obesity and type 2 diabetes.
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Henry, Thomas, Anna Brotcke, David S. Weiss, Lucinda J. Thompson, and Denise M. Monack. "Type I interferon signaling is required for activation of the inflammasome during Francisella infection." Journal of Experimental Medicine 204, no. 5 (April 23, 2007): 987–94. http://dx.doi.org/10.1084/jem.20062665.
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Francisella tularensis is a pathogenic bacterium whose virulence is linked to its ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host-protective multimolecular complex called the inflammasome to release the proinflammatory cytokines interleukin (IL)-1β and -18 and trigger caspase-1–dependent cell death. In this study, we show that cytosolic F. tularensis subspecies novicida (F. novicida) induces a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome-mediated cell death, and release of IL-1β and -18. Extensive type I IFN–dependent cell death resulting in macrophage depletion occurs in vivo during F. novicida infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria monocytogenes but not vacuole-localized Salmonella enterica serovar Typhimurium or extracellular adenosine triphosphate. These results show the specific connection between type I IFN signaling and inflammasome activation, which are two sequential events triggered by the recognition of cytosolic bacteria. To our knowledge, this is the first example of the positive regulation of inflammasome activation. This connection underscores the importance of the cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses.
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Carrasco-Pozo, Catalina, Kah Ni Tan, and Vicky M. Avery. "Hemin Prevents Increased Glycolysis in Macrophages upon Activation: Protection by Microbiota-Derived Metabolites of Polyphenols." Antioxidants 9, no. 11 (November 11, 2020): 1109. http://dx.doi.org/10.3390/antiox9111109.
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Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, upon activation, can prevent cancer development by eliminating neoplastic cells. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for macrophage activation. 3,4-dihydroxyphenylacetic acid (3,4DHPAA) and 4-hydroxyphenylacetic acid (4HPAA), both microbiota-derived metabolites of flavonoids, have not been extensively studied although they exert antioxidant properties. The aim of this study was to determine the effect of hemin on the anticancer properties of macrophages and the role of 3,4DHPAA and 4HPAA in metabolic reprogramming and activation of macrophages leading to the elimination of cancer cells. The results showed that hemin inhibited glycolysis, glycolytic, and pentose phosphate pathway (PPP) enzyme activities and hypoxia-inducible factor-1 alpha (HIF-1α) stabilization, which interferes with macrophage activation (evidenced by decreased interferon-γ-inducible protein 10 (IP-10) release) and their ability to eliminate cancer cells (via cytotoxic mediators and phagocytosis). Hemin also reduced the mitochondrial membrane potential (MMP) and mitochondrial mass in macrophages. 3,4DHPAA and 4HPAA, by stimulating glycolysis and PPP, prevented the impairment of the macrophage anticancer activity induced by hemin. In conclusion, 3,4HPAA and 4HPAA administration could represent a promising strategy for preventing the reduction of macrophage activation induced by hemin.
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Nussbaum, Gabriel, Shimon Ben-Adi, Tamar Genzler, Michael Sela, and Graciela Rosen. "Involvement of Toll-Like Receptors 2 and 4 in the Innate Immune Response to Treponema denticola and Its Outer Sheath Components." Infection and Immunity 77, no. 9 (July 13, 2009): 3939–47. http://dx.doi.org/10.1128/iai.00488-09.
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ABSTRACT Treponema denticola is considered an important oral pathogen in the development and progression of periodontal diseases. In the present study, the mechanisms of recognition and activation of murine macrophages by T. denticola and its major outer sheath protein (MSP) and lipooligosaccharide (LOS or glycolipid) were investigated. T. denticola cells and the MSP induced innate immune responses through TLR2-MyD88, whereas LOS induced a macrophage response through TLR4-MyD88. The presence of gamma interferon (IFN-γ), or of high numbers of T. denticola, circumvented the requirement for TLR2 for the macrophage response to T. denticola, although the response was still dependent on MyD88. In contrast, synergy with IFN-γ did not alter the TLR dependence of the response to the T. denticola surface components LOS and MSP, despite enhanced sensitivity. These data suggest that although there is flexibility in the requirements for recognition of T. denticola cells (TLR2 dependent or independent), MyD88 is a requirement for the downstream signaling events that lead to inflammation. We also demonstrate that both outer sheath molecules LOS and MSP induce macrophage tolerance to further stimulation with enterobacterial lipopolysaccharide. Tolerance induced by T. denticola components during mixed infections may represent a general mechanism through which bacteria evade clearance.
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Zuwała-Jagiello, Jolanta, Monika Pazgan-Simon, Krzysztof Simon, and Maria Warwas. "Picolinic Acid in Patients with Chronic Hepatitis C Infection: A Preliminary Report." Mediators of Inflammation 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/762863.
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Macrophage activation seems to be a feature of chronic liver diseases. Picolinic acid (PA) as a macrophage secondary signal causes the activation of interferon-gamma- (IFN-γ-) prime macrophage and triggers cytokine-driven inflammatory reactions. The rationale for seeking increased PA formation in chronic viral hepatitis is based on the involvement of activated macrophages in chronic viral hepatitis-associated inflammation. The aim of this study was to determine serum PA levels in patients with chronic hepatitis C infection, taking into account the presence of diabetes. We assessed PA and high-sensitivity C-reactive protein (hsCRP) as a marker of inflammation in 51 patients with chronic hepatitis C infection (CHC), both with and without diabetes and 40 controls. Compared with the controls, the patients with CHC showed a significant increase in plasma concentrations of PA and hsCRP (P<0.01andP<0.05, resp.). The values of PA and hsCRP were more elevated in patients with diabetes than without diabetes (bothP<0.01). The positive relationships were between PA and hsCRP levels (P<0.05) and the presence of diabetes (P<0.001). We documented that significant elevation in serum PA levels is associated with diabetes prevalence and increased inflammatory response reflected in hsCRP levels in CHC patients.
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Fehr, Thomas, Gabriele Schoedon, Bernhard Odermatt, Thomas Holtschke, Markus Schneemann, Martin F. Bachmann, Tak W. Mak, Ivan Horak, and Rolf M. Zinkernagel. "Crucial Role of Interferon Consensus Sequence Binding Protein, but neither of Interferon Regulatory Factor 1 nor of Nitric Oxide Synthesis for Protection Against Murine Listeriosis." Journal of Experimental Medicine 185, no. 5 (March 3, 1997): 921–32. http://dx.doi.org/10.1084/jem.185.5.921.
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Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF)1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP−/− and to a lesser degree also IRF2−/− mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-γ in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-γ stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-γ–mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.
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Autenshlyus, Alexander, Sergey Arkhipov, Elena Mikhailova, Igor Marinkin, Valentina Arkhipova, and Nikolay Varaksin. "The Relationship Between Cytokine Production, CSF2RA, and IL1R2 Expression in Mammary Adenocarcinoma, Tumor Histopathological Parameters, and Lymph Node Metastasis." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381988362. http://dx.doi.org/10.1177/1533033819883626.
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Objective: The aim of this study was to evaluate the relationship between cytokine production, GM-CSF receptor (CSF2RA), and IL-1 receptor (IL1R2) expression in mammary adenocarcinoma and their association with it histopathological parameters and lymph node metastasis. Methods: We analyzed tumor biopsy samples (cultured in vitro) from 50 women (aged 43-75) with invasive ductal mammary adenocarcinomas. Enzyme-linked immunosorbent assay method the concentrations of interleukin 2, interleukin 6, interleukin 8, interleukin 10, interleukin 17, interleukin 18, interleukin 1β, interleukin 1Ra, tumor necrosis factor α, interferon γ, granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and vascular endothelial growth factor A were determined in culture supernatants. The expression of CSF2RA and IL1R2 in tumor biopsy was evaluated by immunohistochemical method. Results: We showed that the “cytokine profile” of a tumor (the ability of tumor cells and its microenvironment to produce different cytokines) is very individual. It has been shown that the features of the cytokine profile of the mammary adenocarcinoma are important for the formation and realization of the metastatic potential of the mammary adenocarcinoma. We found correlations between some histopathological parameters of mammary adenocarcinoma and coefficients KGM-CSF/CSF2RA and KIL-1β/IL1R2, which are the ratios of concentrations of granulocyte macrophage colony-stimulating factor and interleukin -1β to expression of CSF2RA and IL1R2, respectively. KGM-CSF/CSF2RA positively correlated with highly differentiated cells, and KIL-1β/IL1R2 positively correlated with the number of mitoses, poorly differentiated cells, and a number of lymph nodes with metastases. KGM-CSF/CSF2RA positively correlated with the concentrations of interleukin 6, interleukin 8, interleukin 1Ra, and granulocyte colony-stimulating factor. KIL-1β/IL1R2 positively correlated with concentrations of interleukin 1β and interferon γ and negative correlated with the concentrations of vascular endothelial growth factor A and tumor necrosis factor α. It is shown that KIL-1β/IL1R2 can be considered as a prognostic indicator predicting the probability of mammary adenocarcinoma metastasis to regional lymph nodes. Conclusions: The ratios of granulocyte macrophage colony-stimulating factor and interleukin 1β cytokines, produced in tumor, to the expression of CSF2RA and IL1R2 depend on levels of interleukin 6, interleukin 8, tumor necrosis factor α, interferon γ, granulocyte colony-stimulating factor, and vascular endothelial growth factor A and are important factors affecting the progression and metastasis of the breast cancer.
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Weinstock-Guttman, Bianca, Jianming Hong, Roseane Santos, Miriam Tamaño-Blanco, Darlene Badgett, Kara Patrick, Monika Baier, et al. "Interferon-β modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients." Multiple Sclerosis Journal 12, no. 5 (September 2006): 541–50. http://dx.doi.org/10.1177/1352458506070605.
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Purpose Multiple sclerosis (MS) patients have a high risk of low bone density. The purpose of this study was to examine the molecular mechanisms potentially capable of modulating bone home-ostasis in response to interferon-β-1a (IFN-β-1a) treatment and the focus was the bone-modulating system comprised of receptor activator of nuclear factor-κB (RANK), its ligand RANKL and its decoy receptor, osteoprotegerin (OPG). Methods In this open-label pharmacodynamic study, peripheral blood was obtained from relapsing remitting MS patients just prior to and at multiple time points after intramuscular injection of 30 μg IFN-β-1a. Samples were analysed for RANKL, tumour necrosis factor related apoptosis-inducing ligand (TRAIL), OPG and macrophage inflammatory protein-1α/β expression. Osteoclast precursor differentiation from peripheral blood cells of MS patients in the presence of exogenously added IFN-β-1a was also assessed. Additionally, the changes in plasma levels of osteocalcin and the C-telopeptides after 1 year of treatment were measured as surrogate markers of bone formation and degradation, respectively. Results IFN-β-1a treatment modulated RANKL and OPG in a selective, time-dependent manner. The levels of OPG protein decreased 25% at the 8-h time point, then increased 43% at the 24-h time point. The levels of free RANKL reached a maximum at the 8-h time point. Increases in the levels of macrophage inflammatory protein-1β (MIP-1β), a chemokine that increases osteolysis, were observed. The levels of the bone formation marker, osteocalcin, were lower in MS patients compared to controls and increased after one year of treatment. Ex vivo treatment of peripheral blood lymphocytes with IFN-β resulted in a marked reduction of osteoclast-like cells in the presence of RANKL and macrophage colony stimulating factor. Conclusions IFN-β treatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients.
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Matte, Christine, and Albert Descoteaux. "Leishmania donovani Amastigotes Impair Gamma Interferon-Induced STAT1α Nuclear Translocation by Blocking the Interaction between STAT1α and Importin-α5." Infection and Immunity 78, no. 9 (June 21, 2010): 3736–43. http://dx.doi.org/10.1128/iai.00046-10.
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ABSTRACT The protozoan parasite Leishmania donovani, the etiological agent of visceral leishmaniasis, is renowned for its capacity to sabotage macrophage functions and signaling pathways stimulated by activators such as gamma interferon (IFN-γ). Our knowledge of the strategies utilized by L. donovani to impair macrophage responsiveness to IFN-γ remains fragmentary. In the present study, we investigated the impact of an infection by the amastigote stage of L. donovani on IFN-γ responses and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in mouse bone marrow-derived macrophages. The levels of IFN-γ-induced expression of major histocompatibility complex class II and inducible nitric oxide synthase (iNOS) were strongly reduced in L. donovani amastigote-infected macrophages. As the expression of those genes is mediated by the transcription factors STAT1α and IFN regulatory factor 1 (IRF-1), we investigated their activation in amastigote-infected macrophages treated with IFN-γ. We found that whereas STAT1α protein levels and the levels of phosphorylation on Tyr701 and Ser727 were normal, IRF-1 expression was inhibited in infected macrophages. This inhibition of IRF-1 expression correlated with a defective nuclear translocation of STAT1α, and further analyses revealed that the IFN-γ-induced STAT1α association with the nuclear transport adaptor importin-α5 was compromised in L. donovani amastigote-infected macrophages. Taken together, our results provide evidence for a novel mechanism used by L. donovani amastigotes to interfere with IFN-γ-activated macrophage functions and provide a better understanding of the strategies deployed by this parasite to ensure its intracellular survival.
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Mulero, Victoriano, and Jeremy H. Brock. "Regulation of Iron Metabolism in Murine J774 Macrophages: Role of Nitric Oxide–Dependent and –Independent Pathways Following Activation With Gamma Interferon and Lipopolysaccharide." Blood 94, no. 7 (October 1, 1999): 2383–89. http://dx.doi.org/10.1182/blood.v94.7.2383.419k20_2383_2389.
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To elucidate the pathways by which nitric oxide (NO) influences macrophage iron metabolism, the uptake, release, and intracellular distribution of iron in the murine macrophage cell line J774 has been investigated, together with transferrin receptor (TfR) expression and iron-regulatory protein (IRP1 and IRP2) activity. Stimulation of macrophages with interferon-γ (IFN-γ) and/or lipopolysaccharide (LPS) decreased Fe uptake from transferrin (Tf), and there was a concomitant downregulation of TfR expression. These effects were mediated by NO-dependent and NO-independent mechanisms. Addition of the NO synthase (NOS) inhibitor N-monomethyl arginine (NMMA) partially restored Fe uptake but either had no effect on or downregulated TfR expression, which suggests that NO by itself is able to affect iron availability. Analysis of the intracellular distribution of incorporated iron revealed that in IFN-γ/LPS-activated macrophages there was a decreased amount and proportion of ferritin-bound iron and a compensatory increase in insoluble iron, which probably consists mainly of iron bound to intracellular organelles. Finally, although NO released by IFN-γ/LPS-activated macrophages increased the iron-responsive element (IRE)-binding activity of both IRP1 and IRP2, IFN-γ treatment decreased IRP2 activity in an NO-independent manner. This study demonstrates that the effect of IFN-γ and/or LPS on macrophage iron metabolism is complex, and is not entirely due to either NO-or to IRP-mediated mechanisms. The overall effect is to decrease iron uptake, but not its utilization.
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Hou, Jiangang, Songjie Cai, Yuya Kitajima, Masayuki Fujino, Hidenori Ito, Kiwamu Takahashi, Fuminori Abe, Tohru Tanaka, Qiang Ding, and Xiao-Kang Li. "5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury." American Journal of Physiology-Renal Physiology 305, no. 8 (October 15, 2013): F1149—F1157. http://dx.doi.org/10.1152/ajprenal.00275.2013.
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Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe2+), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe2+ 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe2+ increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe2+ treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe2+ group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe2+-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe2+ can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.
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Calvi, Sueli A., Angela M. V. C. Soares, Maria Terezinha S. Peraçoli, Marcelo Franco, Raul L. Ruiz, Jussara Marcondes-Machado, Denise Fecchio, Maria C. I. Mattos, and Rinaldo P. Mendes. "Study of bronchoalveolar lavage fluid in paracoccidioidomycosis: cytopathology and alveolar macrophage function in response to gamma interferon; comparison with blood monocytes." Microbes and Infection 5, no. 15 (December 2003): 1373–79. http://dx.doi.org/10.1016/j.micinf.2003.05.001.
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