Role of interleukin‐6 in cardiomyocyte/cardiac fibroblast interactions during myocyte hypertrophy and fibroblast proliferation

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Abstract
The process of cardiac hypertrophy is considered to involve two components: that of cardiac myocyte (CM) enlargement and cardiac fibroblast (CF) proliferation. The interleukin‐6 (IL‐6) family cytokines have been implicated in a variety of cellular and molecular interactions between myocytes and non‐myocytes (NCMs), which in turn have important roles in the development of cardiac hypertrophy. In the study of these interactions, we previously detected very high levels of IL‐6 in supernatants of a “dedifferentiated model” of adult ventricular CMs cultured with CFs. In the present study, we have used this in vitro coculture system to examine how IL‐6 is involved in the interactions between CMs and CFs during CM hypertrophy and CF proliferation. IL‐6 and its signal transducer, 130‐kDa glycoprotein (gp130), were detected by immunostaining cultured CMs and CFs with anti‐IL‐6 or anti‐gp130 antibodies. Addition of anti‐IL‐6 or anti‐gp130 antagonist antibodies into CM/CF cocultures induced a significant decrease in expression of atrial natriuretic peptide (ANP) and β‐myosin heavy chain (β‐MHC) in CMs. The presence of IL‐6 antagonist also resulted in a decrease in the surface area of 12‐day‐old CMs cultured with CFs or in the presence of fibroblast conditioned medium (FCM), and decreased fibroblast proliferation in CM/CF cocultures, particularly in the presence of a gp130 antagonist. The results also show that angiotensin II (AngII) is mainly secreted by CFs and induces IL‐6 secretion in CMs cultured with CFs or with FCM. In addition, the effects of IL‐6 on cardiomyocyte hypertrophy and fibroblast proliferation were inhibited by addition of the AT‐1 receptor antagonist, losartan. These results suggest that IL‐6 contributes significantly to CM hypertrophy by an autocrine pathway and to fibroblast proliferation by a paracrine pathway and that these effects could be mediated by AngII.

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