Extracellular HSP60 induces inflammation through activating and up-regulating TLRs in cardiomyocytes

Jing Tian, Xin Guo, Xue Mei Liu, Li Liu, Qi Fang Weng, Shu Juan Dong, Anne A Knowlton, Wen Jun Yuan, Li Lin

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

AimsThe molecular events leading from cardiomyocyte ischaemia to inflammatory cytokine production are not well understood. We previously found that heat shock protein 60 (HSP60) appeared in extracellular space after cardiomyocyte ischaemia. This study examined the activation and regulation of toll-like receptors (TLRs) by HSP60 in cardiomyocytes.Methods and resultsCytokine production and TLRs regulation mediated by TLRs signalling were examined in response to exogenous HSP60 (exHSP60) and endogenous HSP60 (enHSP60) released extracellularly under ischaemia. The results showed that exHSP60 induced inflammatory cytokine production in adult rat cardiomyocytes and H9c2 cells (a standard cardiac cell line derived from embryonic cells), through a pathway dependent on TLR4, myeloid differentiation factor 88 (MyD88), p38, and nuclear factor-κB (NF-κB). Further study revealed up-regulated expression of both TLR2 and TLR4 by exHSP60, which was dependent on the activation of TLR4, MyD88, c-Jun NH2-terminal kinase (JNK), and NF-κB, but not on p38. In myocytes exposed to ischaemia, enHSP60 was released into the media, and triggered cytokine production and TLR2/4 overexpression, through the same pathways as exHSP60. In rats subjected to LAD ligation, the released enHSP60 contributed to cytokine production and TLR2/4 overexpression in the ischaemic myocardium.ConclusionExtracellular HSP60 induces cytokine production via TLR4-MyD88-p38/NF-κB pathway, and up-regulates TLR2/4 expression via TLR4-MyD88-JNK/NF-κB pathway. Both pathways contribute to myocardial inflammation induced by ischaemia.

Original languageEnglish (US)
Pages (from-to)391-401
Number of pages11
JournalCardiovascular Research
Volume98
Issue number3
DOIs
StatePublished - Jun 1 2013

Keywords

  • Cardiomyocyte
  • Heat shock protein
  • Inflammatory cytokine
  • Toll-like receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

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