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DEFECTIVE IL‐1 SIGNALING RESULTS IN SUPPRESSED INFLAMMATION AND DECREASED REMODELING AFTER MYOCARDIAL INFARCTION
Author(s) -
Bujak Marcin J,
Ren Guofeng,
Dobaczewski Marcin,
Mendoza Leonardo,
Reddy Anilkumar,
Frangogiannis Nikolaos
Publication year - 2007
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.21.6.a1144-a
Subject(s) - chemokine , inflammation , myofibroblast , cytokine , ventricular remodeling , signal transduction , myocardial infarction , medicine , receptor , immunology , endocrinology , microbiology and biotechnology , chemistry , biology , fibrosis
IL‐1 stimulates cytokine and chemokine synthesis, activates leukocytes and modulates fibroblast behavior. All IL‐1‐mediated responses require signaling through the IL‐1 Receptor I (IL‐1RI). IL‐1 expression is induced in the infarcted heart; however, its role in infarct healing remains unknown. In order to investigate the role of IL‐1 signaling on infarct healing and ventricular remodeling, IL‐1RI null mice and WT controls underwent reperfused infarction protocols. Neutrophil, macrophage and myofibroblast infiltration was dramatically attenuated in IL‐1RI null infarcts; however, infarct size and ventricular function were comparable in IL‐1R1−/− mice and WT controls. Infarcted IL‐1RI−/− hearts had reduced cytokine (IL‐6, IL‐10, TGFβ‐1) and chemokine (MCP‐1, MIP‐1α, ‐β, IP‐10) mRNA expression compared with WT hearts and exhibited attenuated dilative remodeling. In vitro experiments demonstrated that IL‐1β stimulation induced MMP‐3 and ‐8 expression and suppressed TIMP‐2 and ‐3 synthesis by isolated cardiac fibroblasts. IL‐1 signaling critically regulates induction of pro‐inflammatory cytokines and chemokines and leukocyte infiltration in myocardial infarction. The protective effects of defective IL‐1 signaling may be related to a suppressed inflammatory response and to an altered MMP:TIMP expression profile in the infarct.