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IL‐10 Improves Cardiomyocyte Survival via Downstream MyD88‐dependent TLR4 Innate Signaling of Jak/Stat3 Pathway
Author(s) -
Bagchi Ashim,
Akolkar Gauri,
Mandal Soma,
Singal Pawan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.553.3
Subject(s) - tlr4 , signal transduction , microbiology and biotechnology , protein kinase b , toll like receptor , biology , tradd , receptor , innate immune system , cancer research , chemistry , apoptosis , programmed cell death , biochemistry , death domain
Recent evidence indicates that changes in the balance between anti‐inflammatory (IL‐10) and pro‐inflammatory (TNF‐α) cytokines is crucial in heart failure. IL‐10 has been shown to antagonize the pro‐apoptotic effect of TNF‐α via the activation of Jak/Stat3 pathway. In parallel, IL‐10‐mediated cardiac cell survival is regulated by the Toll‐like receptor 4 (TLR4) innate signaling where myeloid differentiation gene factor 88 (MyD88) plays a key role. However, interplay between these two signaling cascades is unknown. Our objective was to determine the role of MyD88‐dependent TLR4 innate signaling in acquiring adaptive response to IL‐10 via the Jak/Stat3 pathway. We found an increased TLR4 activity in isolated cardiomyocytes overexpressing MyD88 in presence or absence of IL‐10 treatment. Furthermore, inhibition of TLR4 activity by MyD88‐shRNA suggested that TLR4 activation is dependent on MyD88 which also abrogates downstream Akt Ser86 /Jak/Stat3 pathway. On the contrary, Stat3 inhibition by DPP 5, 15 also suppresses IL‐10‐induced activation of TLR4 by IRAK M (An inhibitor of TLR4 signaling) inhibition; this suggests that Jak/Stat3 via a feedback mechanism also regulates TLR4. In addition, IL‐10 helps in the dissociation of interleukin‐1 receptor activated kinase 4 (IRAK4) into IRAK1 instead of IRAK2 and there was down‐regulation of TNF‐α receptor associated inducible protein (TRAIP) and its associated adaptor molecules TRADD and FADD. Data suggest that MyD88/IRAK1/IRAK4 recruitment, blocks TNF‐αR associated cellular changes and suppresses apoptosis. Up‐regulation of TLR4 signaling by IL‐10 involving Akt‐Jak/Stat3 pathway could be a potential therapeutic strategy in cardiovascular diseases (Supported by CIHR).