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Interactive Role of TLR4 and TLR2 in Cardiac Functions During Stressful Conditions
Author(s) -
Bagchi Ashim K.,
Akolkar Gauri,
Mandal Soma,
Ayyappan Prathapan,
Yang Xi,
Singal Pawan K.
Publication year - 2017
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.31.1_supplement.lb643
Subject(s) - tlr4 , tlr2 , tumor necrosis factor alpha , receptor , downregulation and upregulation , endocrinology , signal transduction , medicine , reperfusion injury , toll like receptor , inflammation , interleukin , cytokine , apoptosis , biology , ischemia , microbiology and biotechnology , innate immune system , biochemistry , gene
An appropriate balance between anti‐inflammatory interleukin‐10 (IL‐10) and pro‐inflammatory tumor necrosis factor‐α (TNF‐α) cytokines has been suggested for a normal functioning of the heart. It has been suggested that toll‐like receptor 4 (TLR4) promotes IL‐10‐mediated cardiac cell survival while another receptor, TLR2, from the same family is detrimental. We examined the interactive role of these two innate signaling molecules (TLR4 and TLR2) under stressful conditions including interleukin‐10 knockout (IL‐10−/−) mice, global ischemia/reperfusion (I/R) injury rat hearts and shRNA experimental models. Circulating and myocardial levels of TNF‐α as well as apoptosis and fibrosis were higher in IL‐10−/− hearts. Increase in TLR2 in IL‐10−/− hearts indicated its negative regulation by IL‐10. The ex‐vivo I/R also caused a marked upregulation of TLR2 and TNF‐α as well as apoptotic and fibrotic signals. However, 40 min reperfusion with IL‐10 in the I/R hearts, triggered an increase in TLR4 expression. Increase in interleukin‐1 receptor‐associated kinase‐M (IRAK‐M) and IRAK‐2 activity during I/R injury suggested their role in TLR2 signaling. Inhibition of TLR4 activity as a consequence of RNAi‐mediated suppression of myeloid differentiation gene 88 (MyD88) suggested a MyD88‐dependent activation of TLR4. Inclusion of IL‐10 during reperfusion, also significantly downregulated the expression of IRAK‐2, TRAIP and apoptotic signals, caspase 3 and Bax/Bclxl ratio. IL‐10 reduced the TNF‐α receptor‐associated increase in TRAIP/TRADD ‐induced apoptosis during ischemia injury which led to an increase in IL‐1β to mitigate TGF‐βRII‐mediated fibrosis. IL‐10 mitigation of these changes suggests that IL‐10 stimulation through TLR4 signaling, dissociates IRAK‐4 into IRAK‐1 instead of IRAK‐2 and may be an important therapeutic approach in restoring heart health from I/R injury. Support or Funding Information Supported by Canadian Institutes of Health Research and Research Manitoba.