title: The inhibition of N-glycosylation of glycoprotein 130 molecule abolishes STAT3 activation by IL-6 family cytokines in cultured cardiac myocytes.
abstract: Interleukin-6 (IL-6) family cytokines play important roles in cardioprotection against pathological stresses. 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. In this study, we examined the biological significance of gp130 glycosylation using tunicamycin (Tm), an inhibitor of enzyme involved in N-linked glycosylation. In cardiomyocytes, the treatment with Tm completely replaced the glycosylated form of gp130 with its unglycosylated one. Tm treatment inhibited leukemia inhibitory factor (LIF)-mediated activation of STAT3 and ERK1/2. Similarly, IL-11 failed to activate STAT3 and ERK1/2 in the presence of Tm. 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. 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. Collectively, these findings indicate that glycosylation of gp130 is essential for signal transduction of IL-6 family cytokines in cardiomyocytes.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Matsuo
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Morihara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Mohri
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Shiho
authors.initials: S
authors.lastname: Murasawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Takewaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakayama
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita City, Osaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D050822:Cytokine Receptor gp130 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006031:Glycosylation; D015850:Interleukin-6 / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000737:chemistry; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014415:Tunicamycin / Q000737:chemistry*
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D014415:Tunicamycin; D050822:Cytokine Receptor gp130; D048049:Extracellular Signal-Regulated MAP Kinases