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Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4
- Source :
- Journal of Biological Chemistry. 286:31308-31319
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
Abstract
- Innate immune response after transient ischemia is the most common cause of myocardial inflammation and may contribute to injury, yet the detailed signaling mechanisms leading to such a response are not well understood. Herein we tested the hypothesis that myocardial ischemia activates interleukin receptor-associated kinase-1 (IRAK-1), a kinase critical for the innate immune signaling such as that of Toll-like receptors (TLRs), via a mechanism that involves heat shock proteins (HSPs) and TLRs. Coronary artery occlusion induced a rapid myocardial IRAK-1 activation within 30 min in wild-type (WT), TLR2(-/-), or Trif(-/-) mice, but not in TLR4(def) or MyD88(-/-) mice. HSP60 protein was markedly increased in serum or in perfusate of isolated heart following ischemia/reperfusion (I/R). In vitro, recombinant HSP60 induced IRAK-1 activation in cells derived from WT, TLR2(-/-), or Trif(-/-) mice, but not from TLR4(def) or MyD88(-/-) mice. Both myocardial ischemia- and HSP60-induced IRAK-1 activation was abolished by anti-HSP60 antibody. Moreover, HSP60 treatment of cardiomyocytes (CMs) led to marked activation of caspase-8 and -3, but not -9. Expression of dominant-negative mutant of Fas-associated death domain protein or a caspase-8 inhibitor completely blocked HSP60-induced caspase-8 activation, suggesting that HSP60 likely activates an apoptotic program via the death-receptor pathway. In vivo, I/R-induced myocardial apoptosis and cytokine expression were significantly attenuated in TLR4(def) mice or in WT mice treated with anti-HSP60 antibody compared with WT controls. Taken together, the current study demonstrates that myocardial ischemia activates an innate immune signaling via HSP60 and TLR4, which plays an important role in mediating apoptosis and inflammation during I/R.
- Subjects :
- Myocardial Ischemia
Ischemia
Apoptosis
chemical and pharmacologic phenomena
Inflammation
Biology
Biochemistry
Cell Line
Mice
Heat shock protein
medicine
Animals
Myocytes, Cardiac
Molecular Biology
Mice, Knockout
Toll-like receptor
Innate immune system
Molecular Bases of Disease
Chaperonin 60
Cell Biology
medicine.disease
Immunity, Innate
Cell biology
Toll-Like Receptor 4
Interleukin-1 Receptor-Associated Kinases
Caspases
Immunology
TLR4
HSP60
Signal transduction
medicine.symptom
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 286
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....43cc61a53c71a2f5f2b86eac3e02ac7d