Interleukin-6 Induces Myogenic Differentiation via JAK2-STAT3 Signaling in Mouse C2C12 Myoblast Cell Line and Primary Human Myoblasts

被引:66
作者
Steyn, Paul J. [1 ]
Dzobo, Kevin [1 ,2 ,3 ]
Smith, Robert I. [1 ]
Myburgh, Kathryn H. [1 ]
机构
[1] Stellenbosch Univ, Dept Physiol Sci & Biochem, ZA-7602 Stellenbosch, South Africa
[2] Univ Cape Town, Cape Town Component, ICGEB, Wernher & Beit Bldg South,Med Campus,Anzio Rd, ZA-7925 Cape Town, South Africa
[3] Univ Cape Town, Inst Infect Dis & Mol Med, Wernher & Beit Bldg South,Med Campus,Anzio Rd, ZA-7925 Cape Town, South Africa
关键词
muscle; myogenesis; satellite cells; myoblasts; IL-6; interleukins; JAK-STAT signaling; differentiation; proliferation; regeneration; MUSCLE SATELLITE CELLS; SKELETAL-MUSCLE; STEM-CELLS; IN-VITRO; TRANSCRIPTIONAL CONTROL; MOLECULAR REGULATION; REGULATORY FACTORS; SOLUBLE RECEPTORS; CANCER CACHEXIA; SELF-RENEWAL;
D O I
10.3390/ijms20215273
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Postnatal muscle growth and exercise- or injury-induced regeneration are facilitated by myoblasts. Myoblasts respond to a variety of proteins such as cytokines that activate various signaling cascades. Cytokines belonging to the interleukin 6 superfamily (IL-6) influence myoblasts' proliferation but their effect on differentiation is still being researched. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is one of the key signaling pathways identified to be activated by IL-6. The aim of this study was to investigate myoblast fate as well as activation of JAK-STAT pathway at different physiologically relevant IL-6 concentrations (10 pg/mL; 100 pg/mL; 10 ng/mL) in the C2C12 mouse myoblast cell line and primary human myoblasts, isolated from eight young healthy male volunteers. Myoblasts' cell cycle progression, proliferation and differentiation in vitro were assessed. Low IL-6 concentrations facilitated cell cycle transition from the quiescence/Gap1 (G0/G1) to the synthesis (S-) phases. Low and medium IL-6 concentrations decreased the expression of myoblast determination protein 1 (MyoD) and myogenin and increased proliferating cell nuclear antigen (PCNA) expression. In contrast, high IL-6 concentration shifted a larger proportion of cells to the pro-differentiation G0/G1 phase of the cell cycle, substantiated by significant increases of both MyoD and myogenin expression and decreased PCNA expression. Low IL-6 concentration was responsible for prolonged JAK1 activation and increased suppressor of cytokine signaling 1 (SOCS1) protein expression. JAK-STAT inhibition abrogated IL-6-mediated C2C12 cell proliferation. In contrast, high IL-6 initially increased JAK1 activation but resulted in prolonged JAK2 activation and elevated SOCS3 protein expression. High IL-6 concentration decreased interleukin-6 receptor (IL-6R) expression 24 h after treatment whilst low IL-6 concentration increased IL-6 receptor (IL-6R) expression at the same time point. In conclusion, this study demonstrated that IL-6 has concentration- and time-dependent effects on both C2C12 mouse myoblasts and primary human myoblasts. Low IL-6 concentration induces proliferation whilst high IL-6 concentration induces differentiation. These effects are mediated by specific components of the JAK/STAT/SOCS pathway.
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页数:30
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