Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.

Hirota, Hisao; Yoshida, Kanji; Kishimoto, Tadamitsu; Taga, Tetsuya

doi:10.1073/pnas.92.11.4862

Cited by 463 publications

(278 citation statements)

References 49 publications

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“…Experimental induction of hemodynamic overload in the adult mammalian heart has been shown to provoke a transient increase in pro-inflammatory cytokines (2). Furthermore, cardiac-specific over expression of IL-6 and TNF-α in mice hearts has been shown to develop cardiac hypertrophy and ventricular dysfunction similar to that seen in human disease conditions, suggesting that cytokines are critically involved in the cardiac remodeling process (9,30).…”

Section: Discussionmentioning

confidence: 99%

“…The aforementioned cytokines play a dual role, activating apoptosis in myocytes (13), while also functioning in a cytoprotective manner (15). Furthermore, inappropriate activation of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) have been recognized as an important mediator in the development of endothelial dysfunction, cardiac hypertrophy, and heart failure in experimental animal models and in humans (9,17,28,30). Atrial natriuretic peptide (ANP) has been shown to inhibit the TNF-α induced adhesion molecule expression in endothelial cells (32).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

2007

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Natriuretic peptide receptor-A (NPRA) is the principal receptor for the cardiac hormones ANP and BNP. Mice lacking NPRA develop progressive cardiac hypertrophy and congestive heart failure. However, the mechanisms responsible for hypertrophic growth in the absence of NPRA signaling are not yet known. In the present study, we determined whether deficiency of NPRA/cGMP signaling alters the cardiac pro-inflammatory cytokines gene expression in Npr1 (coding for NPRA) geneknockout (Npr1 −/− ) mice exhibiting cardiac hypertrophy and fibrosis as compared with control wildtype (Npr1 +/+ ) mice. A significant up-regulation of cytokine genes such as TNF-α (5-fold), IL-6 (3-fold) and TGF-β1 (4-fold) were observed in mutant mice hearts lacking NPRA as compared with the age-matched wild-type mice. In parallel, NF-κB binding activity was almost 5-fold greater in the nuclear extract of Npr1 −/− mutant mice hearts as compared with wild-type Npr1 +/+ mice hearts. Guanylyl cyclase (GC) activity and cGMP levels were drastically reduced by 10-fold and 6-fold, respectively, in ventricular tissues of mutant mice hearts relative to wild-type controls. The present findings provide direct evidence that ablation of NPRA/cGMP signaling activates inflammatory cytokines, probably via NF-κB mediated signaling pathway, and is associated with hypertrophic growth of null mutant mice hearts.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

2007

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“…gp130 also forms part of the receptor-complexes of LIF, OSM, CNTF, IL-11 (Gearing et al, 1992;Ip et al, 1992;Liu et al, 1992;Taga et al, 1992;Fourcin et al, 1994), as well as CT-1 (Pennica et al, 1995). Targeted disruption of gp130 in mice is lethal during early embryogenesis due to impaired myocardial development and hematopoiesis (Yoshida et al, 1996), whereas continuous activation of gp130 in mice transgenic for both IL-6 and the ILdR causes myocardial hypertrophy (Hirota et al, 1995).…”

Section: Structure Of the Interleukin-6 Receptor And Gp130mentioning

confidence: 99%

Interleukin‐6: Structure‐function relationships

et al. 1997

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Interleukin-6 (IL-6) is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response. Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis, and post-menopausal osteoporosis. Hence, selective antagonists of IL-6 action may offer therapeutic benefits. IL-6 is a member of the family of cytokines that includes interleukin-1 1, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and ciliary neurotrophic factor. Like the other members of this family, IL-6 induces growth or differentiation via a receptor-system that involves a specific receptor and the use of a shared signaling subunit, gp130. Identification of the regions of IL-6 that are involved in the interactions with the IL-6 receptor and gp130 is an important first step in the rational manipulation of the effects of this cytokine for therapeutic benefit. In this review, we focus on the sites on IL-6 which interact with its low-affhity specific receptor, the IL-6 receptor, and the high-affinity converter gp130. A tentative model for the IL-6 hexameric receptor ligand complex is presented and discussed with respect to the mechanism of action of the other members of the IL-6 family of cytokines.

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“…and IL-6 receptor in the hearts of transgenic mice was shown to be associated with ventricular hypertrophy and increased JAK/ STAT3 activity (16). Thus, we sought to determine whether CT-1 is also able to activate STAT3 kinase.…”

Section: Pd098059 Does Not Block the Activation Of The Stat3mentioning

confidence: 99%

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

Sheng¹,

Knowlton

Chen³

et al. 1997

Journal of Biological Chemistry

380

212

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Cardiac muscle cell survival plays a critical role in maintaining the normal function of the heart and possibly in cardiac development. Adult cardiac muscle cells are terminally differentiated and therefore have lost their proliferative capacity. In contrast to skeletal muscle, the myocardium does not contain satellite heart muscle cells, and irreversible heart injury results in scarring and an eventual decrease in global cardiac function. In response to mechanical stimuli and hemodynamic stress, the adult myocardium activates an adaptive hypertrophic response that is characterized by an increase in myocardial cell size without a concomitant increase in myocyte number (For review, see Refs. 1 and 2). However, during longstanding exposure to hypertension or other forms of hemodynamic stress, a distinct form of myocardial cell hypertrophy can be activated in which the heart becomes dilated and individual cardiac myocytes exhibit an increase in cell length, reflecting the addition of new sarcomeric units in series (3,4). This dilatation of the heart is usually accompanied by fibrosis, microscarring, and the loss of viable cardiac myocytes throughout the myocardium. As a result of cardiac dilatation and myocyte dropout, the myocardium ultimately develops an irreversible loss of function and ensuing cardiac muscle failure (4). As such, the identification of the signaling pathways that mediate distinct forms of cardiac muscle cell hypertrophy, dysfunction, and cardiac muscle cell survival are critical to the ultimate elucidation of the molecular basis of cardiac muscle failure.By coupling expression cloning with an embryonic stem cellbased model of in vitro cardiogenesis (5), recent studies have identified cardiotrophin 1 (CT-1), 1 a novel cardiac cytokine that was isolated in a search for new factors that induce cardiac myocyte hypertrophy (5). CT-1 is a new member of the IL-6 family of cytokines that exert their biological effects through the shared signaling subunit gp130 (3, 5-7) and can activate a distinct form of myocardial cell hypertrophy that is characteristic of volume overload cardiac hypertrophy at the molecular, morphological, and cellular levels (3). Importantly, cardiotrophin 1 has been shown to be capable of promoting survival of both embryonic and neonatal rat ventricular muscle cells (8). Recent studies have demonstrated that CT-1 exerts its effects on cardiac muscle cell hypertrophy through promoting the heterodimerization of gp130 with the leukemia inhibitory factor

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Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice.

Cited by 463 publications

References 49 publications

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

Enhanced activation of pro-inflammatory cytokines in mice lacking natriuretic peptide receptor-A

Interleukin‐6: Structure‐function relationships

Cardiotrophin 1 (CT-1) Inhibition of Cardiac Myocyte Apoptosis via a Mitogen-activated Protein Kinase-dependent Pathway

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