![]() ![]() Though leptin receptor structurally resembles gp130, utilizing JAK/STAT pathway, the effects of Tm on gp130 signaling in cardiomyocytes remain to be fully addressed. Under the condition of ER stress, protein-tyrosine phosphatase 1B (PTP1B) plays important roles in the suppression of leptin signaling by inhibiting janus kinase (JAK) 2 activity and leptin fails to activate JAK2/STAT3 pathway in the presence of Tm. Interestingly, it was recently demonstrated that ER stress causes leptin resistance. Tm treatment induces ER stress by inhibiting N-glycosylation of cell surface and secreted glycoproteins in the ER and Golgi. Tunicamycin (Tm), an inhibitor of N-acetylglucosamine phosphotransferase, is widely used as an inducer of endoplasmic reticulum (ER) stress. As a result, structural biological studies have proposed the glycosylation sites on gp130 molecule however, the biological significance of the glycosylation of gp130 remains to be fully elucidated in cardiac myocytes. Since the activation of gp130 is essential for the signal transduction of IL-6 family cytokines, the structure of gp130 molecule has been intensively investigated. These cytokines bind their specific receptor α subunits that are expressed in cardiac myocytes and activate their common receptor subunit, glycoprotein 130 (gp130). Among IL-6 family cytokines, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and IL-11, but not IL-6, have been reported to transduce their signals, such as signal transducers and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) 1/2 in cardiac myocytes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist.Īccumulating evidence has demonstrated that interleukin-6 (IL-6) family cytokines play important roles in the maintenance of cardiac homeostasis. All relevant data are within the paper.įunding: This study was supported by a grant-in-aid for scientific research from the Japan society for the promotion of science YF, HN, MM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: The authors confirm that all data underlying the findings are fully available without restriction. Received: ApAccepted: SeptemPublished: October 23, 2014Ĭopyright: © 2014 Matsuo et al. PLoS ONE 9(10):Įditor: Shree Ram Singh, National Cancer Institute, United States of America (2014) The Inhibition of N-Glycosylation of Glycoprotein 130 Molecule Abolishes STAT3 Activation by IL-6 Family Cytokines in Cultured Cardiac Myocytes. Collectively, these findings indicate that glycosylation of gp130 is essential for signal transduction of IL-6 family cytokines in cardiomyocytes.Ĭitation: Matsuo R, Morihara H, Mohri T, Murasawa S, Takewaki K, Nakayama H, et al. To exclude the possibility that Tm blocks LIF and IL-11 signals by inhibiting the glycosylation of their specific receptors, we investigated whether the stimulation with IL-6 plus soluble IL-6 receptor (sIL-6R) could transduce their signals in Tm-treated cardiomyocytes and found that this stimulation was unable to activate the downstream signals. Interestingly, Tm inhibited the activation of JAKs 1 and 2, without influencing the expression of suppressor of cytokine signalings (SOCSs) and protein-tyrosine phosphatase 1B (PTP1B), which are endogenous inhibitors of JAKs. Similarly, IL-11 failed to activate STAT3 and ERK1/2 in the presence of Tm. Tm treatment inhibited leukemia inhibitory factor (LIF)-mediated activation of STAT3 and ERK1/2. In cardiomyocytes, the treatment with Tm completely replaced the glycosylated form of gp130 with its unglycosylated one. In this study, we examined the biological significance of gp130 glycosylation using tunicamycin (Tm), an inhibitor of enzyme involved in N-linked glycosylation. IL-6 cytokines bind to their specific receptors and activate glycoprotein 130 (gp130), a common receptor, followed by further activation of STAT3 and extracellular signal-regulated kinase (ERK)1/2 through janus kinases (JAKs) however the importance of glycosylation of gp130 remains to be elucidated in cardiac myocytes. Interleukin-6 (IL-6) family cytokines play important roles in cardioprotection against pathological stresses. ![]()
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