Literatura académica sobre el tema "HSP27 extracellulaire"

Heat shock of mammalian cells causes protein damage and activates a number of signaling pathways. Some of these pathways enhance the ability of cells to survive heat shock, e.g., induction of molecular chaperones [heat shock protein (HSP) HSP72 and HSP27], activation of the protein kinases extracellular signal-regulated kinase and Akt, and phosphorylation of HSP27. On the other hand, heat shock can activate a stress kinase, c-Jun NH2-terminal kinase, thus triggering both apoptotic and nonapoptotic cell death programs. Recent data indicate that kinases activated by heat shock can regulate synthesis and functioning of the molecular chaperones, and these chaperones modulate activity of the cell death and survival pathways. Therefore, the overall balance of the pathways and their interplay determine whether a cell exposed to heat shock will die or survive and become stress tolerant.

The heat shock protein HSP27 has been correlated in ovarian cancer (OC) patients with aggressiveness and chemoresistance and, therefore, represents a promising potential biomarker for OC diagnosis, prognosis, and treatment response. Notably, secretion of soluble HSP27 has been described by a few cell types and may take place as well in OC cells. Therefore, we studied HSP27 secretion mechanisms under diverse cellular conditions in an OC cell model system. Secretion of HSP27 was characterized after overexpression of HSP27 by transfected plasmids and after heat shock. Intra- and extracellular HSP27 amounts were assessed by Western blotting and ELISA. Protein secretion was blocked by brefeldin A and the impact of the HSP27 phosphorylation status was analyzed overexpressing HSP27 phosphomutants. The present study demonstrated that HSP27 secretion by OVCAR-3 and SK-OV-3 cells depends on intracellular HSP27 concentrations. Moreover, HSP27 secretion is independent of the endoplasmic reticulum secretory pathway and HSP27 phosphorylation. Notably, analysis of OC cell-born exosomes not only confirmed the concentration-dependent correlation of HSP27 expression and secretion but also demonstrated a concentration-dependent incorporation of HSP27 protein into exosomes. Thus, secreted HSP27 may become more important as an extracellular factor which controls the tumor microenvironment and might be a noninvasive biomarker.

The cardiac-specific overexpression of the adenine nucleotide translocase 1 (ANT1) has cardioprotective effects in various experimental heart disease models. Here, we analyzed the link between ANT1 expression and heat shock protein 27 (HSP27)-mediated toll-like receptor 4 (TLR4) signaling, which represents a novel communication pathway between mitochondria and the extracellular environment. The interaction between ANT1 and HSP27 was identified by co-immunoprecipitation from neonatal rat cardiomyocytes. ANT1 transgenic (ANT1-TG) cardiomyocytes demonstrated elevated HSP27 expression levels. Increased levels of HSP27 were released from the ANT1-TG cardiomyocytes under both normoxic and hypoxic conditions. Extracellular HSP27 stimulated TLR4 signaling via protein kinase B (AKT). The HSP27-mediated activation of the TLR4 pathway was more pronounced in ANT1-TG cardiomyocytes than in wild-type (WT) cardiomyocytes. HSP27-specific antibodies inhibited TLR4 activation and the expression of HSP27. Inhibition of the HSP27-mediated TLR4 signaling pathway with the TLR4 inhibitor oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) reduced the mitochondrial membrane potential (∆ψm) and increased caspase 3/7 activity, which are both markers for cell stress. Conversely, treating cardiomyocytes with recombinant HSP27 protein stimulated TLR4 signaling, induced HSP27 and ANT1 expression, and stabilized the mitochondrial membrane potential. The activation of HSP27 signaling was verified in ischemic ANT1-TG heart tissue, where it correlated with ANT1 expression and the tightness of the inner mitochondrial membrane. Our study shows a new mechanism by which ANT1 is part of the cardioprotective HSP27-mediated TLR4 signaling.

Heat shock protein 27 (Hsp27) is a cytoprotective molecule and is inducible via oxidative stress. Anti-cancer therapies, such as the recently investigated gas plasma, subject tumor cells to a plethora of reactive oxygen species (ROS). In ovarian tumor microenvironments (TME), immune cells such as monocytes and macrophages can be found in large numbers and are often associated with cancer progression. Therefore, we quantified extracellular Hsp27 of OVCAR-3 and SK-OV-3 cells after gas plasma exposure in vitro. We found Hsp27 to be significantly increased. Following this, we investigated the effects of Hsp27 on THP-1 monocytes. Live cell imaging of Hsp27-treated THP-1 cells showed decelerated cell numbers and a reduction in cell cluster sizes. In addition, reduced metabolic activity and proliferation were identified using flow cytometry. Mitochondrial ROS production decreased. Using multicolor flow cytometry, the expression profile of eight out of twelve investigated cell surface markers was significantly modulated in Hsp27-treated THP-1 cells. A significantly decreased release of IL18 accommodated this. Taken together, our results suggest an immunomodulatory effect of Hsp27 on THP-1 monocytes. These data call for further investigations on Hsp27’s impact on the interplay of ovarian cancer cells and monocytes/macrophages under oxidative stress conditions.

Heat shock protein 27 (HSP27) is commonly involved in cellular stress. Increased levels of HSP27 as well as autoantibodies against this protein were previously detected in glaucoma patients. Moreover, systemic immunization with HSP27 induced glaucoma-like damage in rodents. Now, for the first time, the direct effects of an intravitreal HSP27 application were investigated. For this reason, HSP27 or phosphate buffered saline (PBS, controls) was applied intravitreally in rats (n = 12/group). The intraocular pressure (IOP) as well as the electroretinogram recordings were comparable in HSP27 and control eyes 21 days after the injection. However, significantly fewer retinal ganglion cells (RGCs) and amacrine cells were observed in the HSP27 group via immunohistochemistry and western blot analysis. The number of bipolar cells, on the other hand, was similar in both groups. Interestingly, a stronger neurofilament degeneration was observed in HSP27 optic nerves, while no differences were noted regarding the myelination state. In summary, intravitreal HSP27 injection led to an IOP-independent glaucoma-like damage. A degeneration of RGCs as well as their axons and amacrine cells was noted. This suggests that high levels of extracellular HSP27 could have a direct damaging effect on RGCs.

Heat-shock protein concentrations in the blood increase after exposure to a variety of stressors, including trauma and psychological stress. Although the physiological function of extracellular heat shock protein remains controversial, there is evidence that extracellular heat shock protein 72 (Hsp72) can facilitate immunologic responses. The signal(s) that mediate(s) the in vivo elevation of extracellular Hsp72 in the blood after stressor exposure remain(s) unknown. Here we report that Hsp72 increases in the circulation via an α1-adrenergic receptor-mediated signaling pathway. Activation of α1-adrenoceptors results in a rapid increase in circulating Hsp72, and blockade of α1-adrenoceptors prevents the stress-induced rise in circulating Hsp72. Furthermore, our studies exclude a role for β-adrenoceptors, glucocorticoids, and ACTH in mediating stress-induced elevations in circulating extracellular Hsp72. Understanding the signals involved in elevating extracellular Hsp72 could facilitate the use of extracellular Hsp72 to bolster immunity and perhaps prevent exacerbation of inflammatory diseases during stress.

Heat shock protein 27 (HSP27) is one of the small molecular chaperones and is involved in many cell mechanisms. Besides the known protective and helpful functions of intracellular HSP27, very little is known about the mode of action of extracellular HSP27. In a previous study, we showed that intravitreal injection of HSP27 led to neuronal damage in the retina and optic nerve after 21 days. However, it was not clear which degenerative signaling pathways were induced by the injection. For this reason, the pathological mechanisms of intravitreal HSP27 injection after 14 days were investigated. Histological and RT-qPCR analyses revealed an increase in endogenous HSP27 in the retina and an activation of components of the intrinsic and extrinsic apoptosis pathway. In addition, an increase in nucleus factor-kappa-light-chain-enhancer of activated B cells (NFκB), as well as of microglia/macrophages and T-cells could be observed. In the optic nerve, however, only an increased apoptosis rate was detectable. Therefore, the activation of caspases and the induction of an incipient immune response seem to be the main triggers for retinal degeneration in this intravitreal HSP27 model.

The recruitment of signal transduction molecules to the membrane is crucial for the efficient coupling of extracellular signals and contractile response. The trafficking is dynamic. We have investigated a possible cross talk between agonist-induced association of translocated RhoA and translocated protein kinase C-α (PKC-α) and a role for heat shock protein 27 (HSP27) in mediating this interaction. Immunoprecipitation with HSP27 monoclonal antibody followed by immunoblotting with either RhoA antibody or PKC-α antibody indicated that acetylcholine induced associations of HSP27-RhoA and HSP27-PKC-α in the membrane fraction but not in the cytosolic fraction. Immunoprecipitation with anti-RhoA monoclonal antibody followed by immunoblotting with PKC-α antibody indicated that acetylcholine induced a significant complexing of RhoA-PKC-α in the membrane fraction but not in the cytosolic fraction. In summary, the data indicate that agonist-induced contraction is associated with 1) association of translocated RhoA with HSP27 on the membrane, 2) association of translocated PKC-α with HSP27 on the membrane, and 3) association of PKC-α with RhoA on the membrane. The data suggest an important role for HSP27 in modulating a multiprotein complex that includes translocated RhoA and PKC-α.

Abstract Myelofibrosis (MF) is the most aggressive myeloproliferative neoplasms (MPN) with the highest degree of morbidity and mortality, including progressive bone marrow fibrosis resulting into bone marrow failure. JAK2 kinase inhibitors have been successfully used for a few years in MPN and more particularly for MF treatment. Despite their beneficial effects on spleen size and symptoms, JAK2 inhibitors induce low molecular and survival responses underscoring the urgent need for other therapeutic approaches. Recently, heat shock protein 90 (HSP90) - known to stabilize JAK2 - has been reported as a promising therapeutic target in MPN. However HSP90 inhibitors show toxicity and induce the expression of stress-inducible proteins like HSP70 and, most likely HSP27 as previously shown in other cancers. In addition, we and others have shown that HSP27, was strongly expressed in patients with idiopathic pulmonary, lung or kidney tubulointerstitial fibrosis, underlying a relevant role of HSP27 in fibrotic processes. Taking into account both the beneficial effects of HSP inhibitors in leukemia and in MPN, and the possible implication of HSP27 in fibrosis, we have evaluated in this work, the status of HSP27 in MF patient's samples and assess the effectiveness of an HSP27 oligonucleotide inhibitor called OGX-427. In this study, we first assessed the extracellular and intracellular level of HSPs from MF patients by ELISA, flow cytometry and by immunohistochemistry. We observed for the first time a specific increase in both intracellular and extracellular HSP27 in CD34+ circulating hematopoietic progenitor cells (n=9-16; P=0.0097) and in the sera of patients (n=24-27; P<0.0001) with MF compared with healthy donors, respectively. Moreover, we identified the presence of HSP27 in the bone marrow's MF patients. We then investigated the in vivo impact of OGX-427, a specific inhibitor of HSP27, or an oligonucleotide control in a murine TPO-induced MF mouse model. The use of OGX-427 limited the progression of the disease in our MF mouse model (n=9). In particular, OGX-427 was associated with a marked reduction in both the spleen weight and size. Also, we noted a decrease of megakaryocyte hyperplasia in the bone marrow accompanied by a visible restoration of spleen structure and lymphoid white pulp territories with OGX-427. Taking altogether, our results support a key role of HSP27 in the pathophysiology in MF and highlight the potential therapeutic benefit of HSP27 inhibitors in this disorder. Disclosures No relevant conflicts of interest to declare.

We have previously reported that endothelin-1 (ET-1) stimulates heat shock protein (HSP) 27 induction in osteoblast-like MC3T3-E1 cells and that p38 mitogen-activated protein (MAP) kinase acts at a point downstream from protein kinase C (PKC) in HSP27 induction. In the present study, we investigated the effect of the adenylyl cyclase-cAMP system on ET-1-stimulated induction of HSP27 in MC3T3-E1 cells. Dibutyryl-cAMP (DBcAMP) dose dependently inhibited the HSP27 accumulation stimulated by ET-1. Forskolin and cholera toxin significantly suppressed the ET-1-stimulated accumulation of HSP27. However, dideoxyforskolin, a forskolin derivative that does not activate cAMP, failed to suppress the ET-1-induced HSP27 accumulation. Forskolin reduced the p38 MAP kinase phosphorylation induced by ET-1 or 12- O-tetradecanoylphorbol-13-acetate (TPA). PGE1, an extracellular agonist that activates cAMP production, reduced the ET-1-induced HSP27 accumulation. In addition, the phosphorylation of p38 MAP kinase induced by ET-1 or TPA was suppressed by PGE1. Forskolin, DBcAMP, and PGE1suppressed the ET-1-stimulated increase in the mRNA level for HSP27. These results indicate that the adenylyl cyclase-cAMP system has an inhibitory role in ET-1-stimulated HSP27 induction in osteoblasts and that the effect is exerted at the point between PKC and p38 MAP kinase in osteoblasts.

La fibrose pulmonaire idiopathique (FPI) est une maladie rare, qui constitue la forme la plus fréquence de pneumopathie interstitielle diffuse de l’adulte. Elle se caractérise par une accumulation massive de matrice extracellulaire, principalement de collagène, dans le parenchyme pulmonaire, ce qui entraine une altération dramatique et irréversible de la fonction respiratoire. La FPI est une pathologie mortelle qui survient principalement après 60 ans, et sa médiane de survie est d’environ 5 ans après diagnostic. Il n’existe aucun traitement curatif. A ce jour seuls 2 médicaments, la pirfénidone et le nintédanib ont été validés dans cette indication, mais ils ne permettent que de ralentir très modérément son évolution. La recherche visant à mieux caractériser les mécanismes physiopathologiques de la FPI ainsi que le développement de nouveaux traitements est donc crucial pour les patients.La maladie se caractérise par la production massive de cellules myofibroblastiques issus de la transformation des autres cellules pulmonaires. Le TGF-b1; est une cytokine clée stimulant cette transformation. On sait que ce processus est régulé, notamment par les cellules de l’immunité dont les macrophages. Les protéines de choc thermique (HSP) et en particulier HSP27 et aB-crystallin sont d’autres modulateurs connus des mécanismes de fibrogenèse.Mon travail de thèse a consisté 1) à étudier l’intérêt de l’utilisation du récepteur macrophagique CD206 comme marqueur diagnostique et comme cible à inhiber pour limiter le développement de la fibrose, 2) à étudier le rôle d’HSP27 présente spécifiquement dans le compartiment extracellulaire dans le développement de la fibrose pulmonaire, 3) à tester les effets d’un oligonucléotide antisens dirigé contre aB-crystallin pour s’opposer au développement de la maladie.Nos travaux ont permis de montrer l’augmentation de l’expression du récepteur macrophagique CD206 en cas de fibrose dans les macrophages pulmonaires humains et murins. Le traitement des macrophages par un radiotraceur dirigé sur le CD206, le tilmanocept permet de quantifier son expression, et celle-ci est diminuée par le nintédanib, et par un inhibiteur des macrophages M2, le tofacitinib. Le traitement par tofacitinib permet aussi de limiter le développement de la fibrose chez la souris, tout en limitant le recrutement des macrophages. Ce travail suggère l’utilité du CD206 pour le diagnostic de la FPI et l’intérêt de développer des inhibiteurs pour le traitement de la fibrose. Dans la 2è partie, mes travaux montrent qu’HSP27 est sécrétée par les cellules pulmonaires en conditions pro-fibrosantes, qu’elle est capable alors d’interagir avec les récepteurs TLR2 et TLR4. La conséquence est une potentialisation de la transformation myofibroblastique des cellules pulmonaires induite par le TGF-b1;. HSP27 sécrétée par les cellules pulmonaires induit aussi une activation des cellules macrophagiques et l’expression de cytokines pro-fibrosantes. Nous avons montré qu’HSP27 se comporterait comme un médiateur intercellulaire pro-fibrosant, et que son inhibition constituait un intérêt pour limiter le développement de la maladie. Dans la 3ème partie de ce travail, nous avons testé un oligonucléotide antisens dirigé contre aB-crystallin et modifié par conjugaison lipidique. Ce travail n’a pas montré l’intérêt de ce composé vis-à-vis de l’oligonucléotide de première génération pour limiter les processus profibrosants.En conclusion, mon travail a permis d’ouvrir de nouvelles pistes de diagnostic et de traitement en relation avec un récepteur macrophagique le CD206 et une protéine de choc thermique HSP27
Idiopathic pulmonary fibrosis (IPF) is a rare, chronic and progressive parenchymal lung disease of unknown origin, the most abundant form of adult interstitial lung diseases (ILD). It is characterized by myofibroblast proliferation and an increase in extracellular matrix production, mainly collagen into pulmonary parenchyma that dramatically and irreversibly impaired respiratory function. IPF is a fatal disease, with a median survival time around 5 years after diagnosis, and which occurs mainly after 60 years. Except pirfenidone and nintedanib that may slightly delay clinical worsening, no pharmacologic treatment is currently available. It becomes crucial that laboratories continue their work exploring new pathways of interest in IPF and propose new and efficient therapeutic targets/drugs for fibrosis.TGF-b1 is a key cytokine to orchestrate fibrosis by favoring myofibroblast proliferation and differentiation. This phenomenon is regulated partially by immune cells including macrophages. Heat shock proteins (HSP), notably HSP27 and aB-crystallin, are other mediators known to be involved in fibrogenesis. My thesis work consisted in 1) studying the interest of macrophagic receptor CD206 as diagnosis marker and target to limit fibrosis progression, 2) investigating the role of extracellular HSP27 in the development of lung fibrosis, 3) testing the effect of an antisens oligonucleotide against aB-crystallin to limit efficiently disease progression.Our work shows the increase of CD206 expression in fibrotic conditions in human and mouse macrophages. The use of radiotracer detecting specifically CD206, 99mTc-Tilmanocept, is able to quantify it. Interestingly, radioactive signal is decreased by nintedanib treatment as well as by M2 macrophages inhibitor, tofacitinib, in mice treated by bleomycin. In addition, tofacitinib treatment is also able to limit the development of lung fibrosis by limiting macrophage infiltration and CD206 expression. This work suggests to use CD206 to IPF diagnosis and the interest to develop CD206 inhibitors to treat lung fibrosis. In the second part, my work highlights HSP27 secretion by pulmonary cells in pro-fibrotic conditions and the colocalisation of this protein with TLR2 and 4. In consequence of the increase in extracellular HSP27 concentration, we observe that myofibroblastic transition of pulmonary cells, induced by TGF-b1 treatment, is potentiated. Furthermore, HSP27 secretion by lung cells also induces macrophage activation and their expression of pro-fibrotic cytokines. In addition, we show that its depletion limits myofibroblast transition induced by TGF-b1. Ours results assed that extracellular HSP27 is a pro-fibrotic intercellular mediator, which inhibition may be useful to reduce pulmonary fibrosis progression. In the last part, we compare a lipid modified antisens oligonucleotide against aB-crystallin with the first generation one. Unfortunately, our results do not show a real interest of this compound compared to the first generation one for limiting pulmonary fibrotic processes.To conclude, my thesis works suggest new diagnosis and treatment options for pulmonary fibrosis by inhibiting macrophagic CD206 receptor and extracellular form of HSP27

In recent years, compelling evidence has accumulated suggesting heat shock proteins (HSPs) which are generally believed to be localised and functioning mainly within eukaryotic cells as cyto-protective molecular chaperones, are also localised in the extracellular milieu. Depending on their localisation, on the cell surface (membrance-bound or embedded), or in the peripheral circulation, extracellular HSPs may induce apoptotic cell death, or in contrast protect cells from cell damage and/or cell death when exposed to cellular stress, or may even elicit a stimulatory effect on the innate immune response including cell activiation and cytokine secretion. Hence, the localisation of intracellular and extracellular HSPs appears to be critical in determining their roles in terms of stimulating cell death, cyto-protection, or immune activiation under normal physiological conditions and following exposure to stress stimuli. This thesis describes the intracellular expression, up-regulation, and cell surface localisation of endogenous HSPs: HSP27, Hsp60, Hsp72 and Hsp90 by flow cytometry, florescence microscopy and Western blotting, under control conditions and in response to environmental stress using in vitro and ex vivo models with the intention of determining their physiological roles. The ability of extracellularly administered HSPs (Hsp70 and Hsp72) to protect cultured U937 cells in vitro or peripheral primary human leukogytes or erythrocytes ex vivo from various stress stimuli was demonstrated and was found to be dependent on surface binding and/or internalisation via scavenger receptors (SRs) or phosphatidylserine (PS), which could be blocked by receptor specific ligands. Extracellular HSPs were also shown to be able to stimulate an immune response through the induction of U937 monocyte differentiation into macrophages as evidenced through the up-regulation of the surface receptors: CD36, SR-A1 and CD91 analysed by flow cytometry. These proteins were able to stimulate TNF-x and IL-10 production and secretion by U937 macrophages, shown by ELISA, and chemotatic properties were demonstrated using Boyden chambers. The cyto-protective and immune regulatory effects of extracellular HSPs have potential therapeutic value as treatments in a wide variety of clinical situations.

博士
高雄醫學大學
醫學研究所博士班
103
Background: Sepsis, the leading cause of death in intensive care units, annually affects more than 500,000 patients in the United States; despite advances in treatment and supportive care, the mortality rate remains higher than 20%. Our previous study revealed that heat shock reduces the sepsis-related mortality rate by increasing the expression of heat shock protein 72 (Hsp72, also known as Hp70). Hsp72, a molecular chaperone intracellularly induced by stress, exhibits antiinflammatory and antiapoptotic effects. Hsp72 protects cells and is released into the circulation by various cells in response to stress and toxic treatments. However, the precise role of extracellular Hsp72 (eHsp72) during sepsis remains unclear . The present study was divided into two parts; the first part was conducted to clarify the effect of eHsp72 on the sepsis-related survival rate and to determine the underlying factors. The second part was conducted to assess the hypothesis that eHsp72 is involved in reversing sepsis-induced liver dysfunction. Methods: Part 1: Sepsis was induced by cecal ligation and puncture (CLP). Changes in serum levels of Hsp72 and cytokines were determined during sepsis, and the results were correlated with the survival rate. The effects of heat pretreatment on Hsp72 expression in septic rat leukocytes and those of septic rat serum, lipopolysaccharide (LPS), and certain cytokines on Hsp72 expression in macrophage NR8383 cells were 7 determined. Part II: Liver function was determined on the basis of changes in the enzymatic activities of serum glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). Apoptosis was measured using terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression of Bcl-2, Bax, cleaved caspase-3 and -9, and cleaved poly(ADP ribose) polymerase (PARP) in liver tissue was analyzed using W estern blotting. Results: Part 1: Circulating Hsp72 levels increased during sepsis (0, 5.5, 6.5, 10, and 6.5 ng/mL at 0, 3, 6, 9, and 18 h after CLP), positively correlating with survival rates. LPS triggered Hsp72 expression in heat-pretreated rats. Heat pretreatment also increased Hsp72 expression in nonseptic (535%, p < 0.01) and septic (116%, p < 0.01) rat leukocytes. Furthermore, incubating the serum of septic rats with NR8383 cells increased eHsp72 levels in a cultured medium. Cytokine profiling revealed that among the 19 cytokines screened, the levels of cytokine-induced neutrophil chemoattractant 3 (211.3%, p < 0.05), interleukin-10 (147%, p < 0.05), monocyte chemotactic protein 1 (MCP-1; 49.6%, p < 0.05), and tumor necrosis factor alpha (51.8%, p < 0.05) increased. MCP-1 and LPS released Hsp72 from NR8383 cells. Part II: The results revealed that GOT and GPT activities increased by 126% and 121%, respectively, during sepsis and returned to the control level following the administration of recombinant human Hsp72 (rhHsp72). During sepsis, apoptotic cells 8 in liver tissue were augmented (665.7%, p < 0.01); however, the effect was reversed on treatment with rhHsp72. Furthermore, during sepsis, Bcl-2/Bax protein expression in liver tissue was downregulated (&;#8722;26%; p < 0.01), and the downregulation was diminished after rhHsp72 treatment. Moreover, during sepsis, expression of cleaved capase-3, cleaved caspase-9, and PARP in liver tissue was upregulated by 40.9%, 103.3%, and 1106%, respectively, and the upregulation was reversed after treatment with rhHsp72. Conclusion: These results demonstrate that increases in levels of circulating Hsp72 improved the survival rate during sepsis. The increases in circulating Hsp72 may be mediated through MCP-1 and/or LPS. Moreover, during sepsis, eHsp72 restored liver function by ameliorating apoptosis through the mitochondria-initiated caspase pathway . Our findings provide a biochemical basis for the development of rhHsp72 as a therapeutic agent for sepsis management.