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

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.

Interleukin-6 Receptor Signaling Disruption Prevents Cardiac Allograft Deterioration in Mice

“…These findings also are consistent with those of previous in vitro studies in which blocking IL-6 receptor signaling decreased cardiac fibroblast proliferation. 9 Beside its roles in fibrosis, IL-6 is also a potent modulator of immune responses in multiple cell types of both the innate and adaptive systems. [28][29][30] Hence, it is possible that blocking IL-6 receptor signaling ameliorates chronic rejection in this model through immunomodulatory effects.…”

“…Elevated IL-6 levels in a donor's heart, kidney, and liver have been shown to worsen ischemia-reperfusion injury in recipients, resulting in deteriorating organ function. 7,8 Although advances in immunosuppressive drugs have greatly decreased the incidence of acute graft rejection and chronic rejection 9 remain a barrier to long-term graft survival. 10 Chronic rejection of cardiac allografts manifests as interstitial fibrosis, vascular occlusion, and progressive deterioration of graft function.…”

Cardiac fibroblasts influence cardiomyocyte phenotype in vitro

“…In vitro studies have established that signals induced by myocardial injury affect fibroblasts and cardiomyocytes and may regulate the degree of fibrosis and hypertrophy associated with the recovery process (16,17,20,32). For example, complex cytokine-mediated interactions dissected in vitro revealed activation of mitosis in cardiomyocytes with concomitant suppression of fibroblast proliferation.…”

“…For example, complex cytokine-mediated interactions dissected in vitro revealed activation of mitosis in cardiomyocytes with concomitant suppression of fibroblast proliferation. These intercellular signals, e.g., interleukin (IL)-1␤, IL-6, and transforming growth factor (TGF)-␤, as well as various undefined soluble factors, may be of nonmyocardial, epicardial, or myocardial in vivo origin and act through paracrine or autocrine pathways (16,17,25,32,37,(41)(42)(43). Important cardiac fibroblast-cardiomyocyte interactions have been demonstrated in appositional cocultures involving direct membrane contact and/or cell fusion as well as through the use of noncontact cell culture paradigms to assess the role of soluble factors (12,13,17,42).…”

Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease

“…We hypothesize that the attenuation of heart hypertrophy likely results from the lower plasma levels of IL-6, inasmuch as a similar reduction in IL-6 was observed in both BERK BM / low TF and BERK BM /Tie2 Cre 1 mice compared with sickle mice with normal TF expression. Indeed, IL-6 triggers hypertrophic growth of cardiomyocytes, 18 induces proliferation of cardiac fibroblasts, 19 contributes to heart hypertrophy in various mouse models, [20][21][22] and is a marker of cardiovascular disease.…”