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.
Highlights
Accumulating evidence has demonstrated that interleukin-6 (IL6) family cytokines play important roles in the maintenance of cardiac homeostasis [1]
Since Tm is an inhibitor of N-acetylglucosamine phosphotransferase, we examined the effects of Tm on the glycosylation of gp130 in cultured cardiac myocytes
We have demonstrated that Tm inhibited activation of STAT3 and ERK1/2 by leukemia inhibitory factor (LIF) and IL-11; we cannot completely rule out the possibility that the glycosylation of the endogenous LIF receptor (LIFR) and IL-11R might be modulated by Tm and lose the capacity of activating gp130, though the molecular weight of some fraction of LIFR and/or IL-11R was not apparently affected by Tm (Figure 1)
Summary
Accumulating evidence has demonstrated that interleukin-6 (IL6) family cytokines play important roles in the maintenance of cardiac homeostasis [1]. 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) and extracellular signal-regulated kinase (ERK) 1/2 in cardiac myocytes [2,3]. These cytokines bind their specific receptor a subunits that are expressed in cardiac myocytes and activate their common receptor subunit, glycoprotein 130 (gp130) [4]. Though leptin receptor structurally resembles gp130, utilizing JAK/STAT pathway [9], the effects of Tm on gp130 signaling in cardiomyocytes remain to be fully addressed
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
