Adiponectin Induces Interleukin-6 Production and Activates STAT3 in Adult Mouse Cardiac Fibroblasts

Background Information: APN (adiponectin), an adipocyte-derived cytokine highly presented in serum, which exerts antidiabetic, anti-atherosclerotic and cardioprotective actions, also enhances CFB (cardiac fibroblast) proliferation and protects against cardiac fibrosis. STAT3 (signal transducer and activator of transcription 3), a major mediator in the gp130/JAK2 (Janus kinase 2)/STATs signalling pathway, plays a critical role in cardioprotective events. Almost two-thirds of total myocardial cells are CFBs; however, whether APN regulates STAT3 signalling pathway has not been clarified yet in CFBs. In the present study, we investigated the effect of recombinant globular APN on the STAT3 activity in adult mouse CFBs and explored the possible signalling transduction mechanism.

Results: In cultured CFBs, APN (10 microg/ml) can significantly induce delayed STAT3 Tyr(705) phosphorylation time-dependently, up to 60 min, and mediate STAT3 translocation from cytoplasm to nucleus. Transfection of siRNA (small interfering RNA) specific for AdipoR1 (APN receptor 1), but not AdipoR2, obviously inhibited APN-induced STAT3 Tyr(705) phosphorylation, indicating that AdipoR1, not AdipoR2, is required for STAT3 phosphorylation. Both inhibition of gp130 by anti-gp130 neutralizing antibody and JAK2 by AG490 (a specific inhibitor for JAK2) can inhibit APN-induced STAT3 phosphorylation and STAT3 transcription activity detected using 2 x pAPRE-Luc (APRE reporter) assay. Furthermore, we found that the IL (interleukin)-6 level in culture medium was significantly increased after stimulation with APN and the IL-6 mRNA level was also markedly increased in CFBs, which can be reversed by siRNA for AdipoR1, but not for AdipoR2, and that anti-IL-6 neutralizing antibody can significantly inhibit APN-induced STAT3 Tyr(705) phosphorylation.

Conclusions: APN induces IL-6 production mediated by AdipoR1, not AdipoR2, in adult mouse CFBs, which leads to the stimulation of the gp130/JAK signalling pathway, and as a result causes STAT3 activation.