Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals

Pockley, A. Graham

doi:10.1054/csac.1998.0121

Cited by 89 publications

(72 citation statements)

References 37 publications

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“…HSP60 has been found in the plasma of healthy individuals with 25% of them having levels similar or higher to the concentrations used in the current study 11. In addition, we have found HSP60 in the plasma of rats, although levels were much lower than those reported in British civil servants, but the intra-cardiac levels were likely much higher 29.…”

Section: Discussionsupporting

confidence: 64%

“…After pilot experiments to test several time-points, cardiac myocytes were treated for 16h with both rat and rhHSP60 (1 ug/ml). This concentration of HSP60 was based on the report that 25% of British civil servants enrolled in the Whitehall study had 1.0 :g/ml or more of HSP60 present in their serum 11. As shown in Figure1C, both rat and rhHSP60 activated caspase 3.…”

Section: Resultsmentioning

confidence: 89%

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Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis

Kim

Stice

Chen

et al. 2009

Circulation Research

144

137

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Rationale: Previously, we have found that changes in the location of intracellular heat shock protein (HSP)60 are associated with apoptosis. HSP60 has been reported to be a ligand of Toll-like receptor (TLR)-4. Objective: We hypothesized that extracellular HSP60 (exHSP60) would mediate apoptosis via TLR4. Methods and Results: Adult rat cardiac myocytes were treated with HSP60, either recombinant human or with HSP60 purified from the media of injured rat cardiac myocytes. ExHSP60 induced apoptosis in cardiac myocytes, as detected by increased caspase 3 activity and increased DNA fragmentation. Apoptosis could be reduced by blocking antibodies to TLR4 and by nuclear factor B binding decoys, but not completely inhibited, even though similar treatment blocked lipopolysaccharide-induced apoptosis. Three distinct controls showed no evidence for involvement of a ligand other than exHSP60 in the mediation of apoptosis. Conclusions: This is the first report of HSP60-induced apoptosis via the TLRs. HSP60-mediated activation of TLR4 may be a mechanism of myocyte loss in heart failure, where HSP60 has been detected in the plasma. (Circ Res. 2009;105:1186-1195.)Key Words: Toll-like receptor-4 Ⅲ apoptosis Ⅲ heat shock protein 60 Ⅲ cardiac myocytes Ⅲ tumor necrosis factor Ⅲ TLR4 Ⅲ inflammation T oll-like receptors (TLRs) have been recognized in the last 15 years as an important part of the immune system. The TLRs are a key component of innate immunity, a primitive immunity characterized by the rapid recognition of bacterial and other motifs as dangerous, followed by an inflammatory response that includes the production of cytokines, such as tumor necrosis factor (TNF)-␣. Heat shock protein (HSP)60 is thought to be a ligand of TLR4, which has been found on the surface of cardiac myocytes. 1,2 In the immune system, activation of TLR4 is characterized by activation of nuclear factor (NF)B followed by production of TNF-␣. Limited studies have addressed the function of the TLRs in nonimmune system cells. We hypothesized that extracellular (ex)HSP60 activated TLR4 and that this would induce cardiac myocyte apoptosis.Lipopolysaccharide (LPS) has also been identified as a ligand for TLR4. Some controversy persists as to whether observed effects with other proteins activating TLR4 do so directly, or are actually contaminated with LPS. 3 However, it is becoming clear that extracellular HSPs have an important role in cell signaling. 4 To address the issue of LPS contamination, in addition to careful controls, we examined the effect of LPS on apoptosis, and the effect of a TLR4 blocking antibody on the LPS and exHSP60 induced apoptosis.We report here that exHSP60 binds selectively to the cardiac myocyte and induces apoptosis. Apoptosis is decreased by anti-TLR4 blocking antibodies but not by blocking antibodies to TLR-2 or CD14. These findings imply that HSP60 released during cardiac injury can have a paracrine effect on neighboring myocytes leading to cell death. This is the first report of HSP60 having a toxic effect on cardiac myocyte...

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Section: Discussionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 89%

Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis

Kim

Stice

Chen

et al. 2009

Circulation Research

144

137

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“…Circulating HSP60 has been hypothesized to play a role in atherosclerosis by inducing inflammation and autoimmune mechanisms (see recent reviews97, 98). The presence of HSP60 in the blood of normal patients was first described in 1999 99. Recent studies have investigated the relationship between chronic heart failure severity and serum HSP60 levels 64.…”

Section: Cardiac Chaperones Are Regulated In the Pathophysiology Of Amentioning

confidence: 99%

Hold Me Tight

2010

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“…The presence of antibodies and T cells that are reactive to Hsp60 or Hsp65 in pathophysiological conditions suggests that these proteins play an important role as cellular targets in autoimmunity due to an existing similarity between the bacterial antigen and the autologous protein [16]. On the other hand, high anti-Hsp60/65 antibody titers were not found to be restricted to disease conditions and could also be detected in supposedly healthy individuals as they aged [17], [18]. Indeed, autoantibodies can be indicators of susceptibility to the future development of various autoimmune diseases [19], [20], [21], [22].…”

Section: Introductionmentioning

confidence: 99%

Administration of Mycobacterium leprae rHsp65 Aggravates Experimental Autoimmune Uveitis in Mice

et al. 2009

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The 60kDa heat shock protein family, Hsp60, constitutes an abundant and highly conserved class of molecules that are highly expressed in chronic-inflammatory and autoimmune processes. Experimental autoimmune uveitis [EAU] is a T cell mediated intraocular inflammatory disease that resembles human uveitis. Mycobacterial and homologous Hsp60 peptides induces uveitis in rats, however their participation in aggravating the disease is poorly known. We here evaluate the effects of the Mycobacterium leprae Hsp65 in the development/progression of EAU and the autoimmune response against the eye through the induction of the endogenous disequilibrium by enhancing the entropy of the immunobiological system with the addition of homologous Hsp. B10.RIII mice were immunized subcutaneously with interphotoreceptor retinoid-binding protein [IRBP], followed by intraperitoneally inoculation of M. leprae recombinant Hsp65 [rHsp65]. We evaluated the proliferative response, cytokine production and the percentage of CD4+IL-17+, CD4+IFN-γ+ and CD4+Foxp3+ cells ex vivo, by flow cytometry. Disease severity was determined by eye histological examination and serum levels of anti-IRBP and anti-Hsp60/65 measured by ELISA. EAU scores increased in the Hsp65 group and were associated with an expansion of CD4+IFN-γ+ and CD4+IL-17+ T cells, corroborating with higher levels of IFN-γ. Our data indicate that rHsp65 is one of the managers with a significant impact over the immune response during autoimmunity, skewing it to a pathogenic state, promoting both Th1 and Th17 commitment. It seems comprehensible that the specificity and primary function of Hsp60 molecules can be considered as a potential pathogenic factor acting as a whistleblower announcing chronic-inflammatory diseases progression.

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Identification of human heat shock protein 60 (Hsp60) and anti-Hsp60 antibodies in the peripheral circulation of normal individuals

Cited by 89 publications

References 37 publications

Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis

Extracellular Heat Shock Protein 60, Cardiac Myocytes, and Apoptosis

Hold Me Tight

Administration of Mycobacterium leprae rHsp65 Aggravates Experimental Autoimmune Uveitis in Mice

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