Extracellular heat shock protein 70 inhibits tumour necrosis factor-α induced proinflammatory mediator production in fibroblast-like synoviocytes

Abstract

Introduction It was recently suggested that heat shock protein (HSP)70, an intracellular protein, is a potential mediator of inflammatory disease when it is released into the extracellular compartment. Although elevated HSP70 levels have been identified in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid compared with patients with osteoarthritis and healthy individuals, it remains unclear what role extracellular HSP70 plays in the pathogenesis of RA. This study was conducted to investigate the effects of extracellular HSP70 on the production of RA-associated cytokines in fibroblast-like synoviocytes from patients with RA and to elucidate the mechanisms involved. Methods IL-6, IL-8 and monocyte chemoattractant protein (MCP)-1 levels in culture supernatants were measured using enzyme-linked immunosorbent assays. Activation of mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated protein kinases (ERKs), c-Jun amino-terminal kinase (JNK) and p38 MAPK, was detected using Western blotting. Nuclear translocation of nuclear factor-κB (NF-κB) and degradation of the inhibitory protein IκBα were examined using immunohistochemistry and Western blotting. Results Human HSP70 downregulated IL-6, IL-8 and MCP-1 production in RA fibroblast-like synoviocytes induced by tumour necrosis factor (TNF)-α in a concentration dependent manner. HSP70 inhibited the activation of ERK, JNK and p38 MAPK in fibroblast-like synoviocytes stimulated by TNF-α. Furthermore, HSP70 also significantly inhibited nuclear translocation of nuclear factor-κB and degradation of IκBα induced by TNF-α. Conclusion Extracellular HSP70 has an anti-inflammatory effect on RA by downregulating production of IL-6, IL-8 and MCP-1 in fibroblast-like synoviocytes, which is mediated through inhibited activation of the MAPKs and NF-κB signal pathways.

Exogenous heat shock protein-70 inhibits cigarette smoke-induced intimal thickening

“…In agreement with our study, treatment with HSP70 alone had no effect. The results of our in vitro experiments with RASMC support the in vivo findings in mice and confirm the findings by Luo et al (25) in human FLS. How extracellular HSP70 modulates ERK activation remains unknown.…”

“…The reduction in PCNA expression by rHSP70 treatment was not coupled with significant changes in p21 expression (8). A report by Luo et al (25) showed similar results with human fibroblast-like synoviocytes (FLS) isolated from patients with rheumatoid arthritis. In their study, FLS stimulated with TNF-␣ had reduced ERK activation and decreased inflammatory signaling with increasing amounts of HSP70.…”

Extracellular heat shock protein 70 (HSPA1A) and classical vascular risk factors in a general population

“…The unanswered question, asked by Hooper and Hoopet 2004, remains: are low levels of Hsp70 the cause or the consequence of atherosclerosis? Taking into consideration that Hsp70 (HSPA1A) has anti-inflammatory properties due to the inhibition of the expression of proinflammatory cytokines (Luo et al 2008) and of proinflammatory transcription factors such as the nuclear κβ factor by blocking target, activation, and binding (Stice and Knowlton 2008), low levels of Hsp70 (HSPA1A) would promote a proinflammatory state and increase the vulnerability of the arterial wall to the damaging action of vascular risk factors involved in endothelial dysfunction, the first stage in the development of the atherosclerotic plaque. On the other hand, low levels of Hsp70 (HSPA1A) may be the result of the endothelial dysfunction that entails a reduction in the production of NO, a powerful inducer of protein synthesis (Pockley et al 2003).…”

Effects of HSP70 on the compression force-induced TNF-α and RANKL expression in human periodontal ligament cells

“…A recent study found that human HSP70 inhibited the expression of pro-inflammatory cytokines such as interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1 in rheumatoid arthritis fibroblast-like synoviocytes (RA FLSs) [12]. The authors suggested that there is an inverse relationship between HSP expression and TNF-a and RANKL expression.…”