Role of interleukin-6 in cardiomyocyte/cardiac Fibroblast Interactions During Myocyte Hypertrophy and Fibroblast Proliferation

J Cell Physiol. 2005 Aug;204(2):428-36. doi: 10.1002/jcp.20307.

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 beta-myosin heavy chain (beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Antigens, CD / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Cytokine Receptor gp130
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Hypertrophy
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / metabolism
  • Interleukin-6 / physiology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology*
  • Receptor, Angiotensin, Type 1 / metabolism
  • Tissue Distribution

Substances

  • Antigens, CD
  • Il6st protein, mouse
  • Interleukin-6
  • Membrane Glycoproteins
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Cytokine Receptor gp130