title: Beneficial synergistic interactions of TNF-alpha and IL-6 in C2 skeletal myoblasts--potential cross-talk with IGF system.
abstract: The interaction effects of tumour necrosis factor-alpha (TNF-alpha) and interlukin-6 (IL-6) on skeletal muscle proliferation and differentiation remains controversial. We therefore investigated the potential interactive effects of TNF-alpha and IL-6 on murine C2 skeletal myoblast survival, differentiation and proliferation. A novel and unexpected positive temporal interaction between TNF-alpha and IL-6 on cell growth was identified (90%), with maximal beneficial effects obtained in myoblasts treated with TNF-alpha (10 ng/ml) for 24 h prior to being dosed with IL-6 (2.5 ng/ml) for a further 24 h. This combined treatment significantly (p < 0.05) increased the level of total cellular protein (330%), extracellular signal-regulated kinase (ERK) phosphorylation (55%), and S-phase of cell cycle (2.5-fold), confirming cell growth. The expression of mRNAs of key regulators of muscle mass: insulin-like growth factor binding protein-5, insulin-like growth factor-II (IGF-II), IGF-I receptor (IGF-IR) and IGF-II receptor (IGF-IIR) were also significantly (p < 0.05) increased by 1600-, 1.6-, 27- and 6-fold, respectively, giving an indication of the regulatory mechanisms of this interaction. Moreover, in response to this treatment, the expression level of signal-transducing glycoprotein 130 (gp130) was induced up to 3.5-fold but not after either treatments alone. This may not only explain the beneficial effects of this treatment on skeletal myoblast numbers but also define a functional role of gp130 in skeletal muscle cells. Our data suggest that in the presence of TNF-alpha/IL-6 functions positively and potentially also cooperatively with the IGF system to achieve the maximal beneficial effect on skeletal myoblast numbers.
authors.affiliation: Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Cheshire, England, UK. n.al-shanti@mmu.ac.uk
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Shanti
authors.forename: Amarjit
authors.initials: A
authors.lastname: Saini
authors.forename: Steve H
authors.initials: SH
authors.lastname: Faulkner
authors.forename: Claire E
authors.initials: CE
authors.lastname: Stewart
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D013002:Somatomedins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018975:Insulin-Like Growth Factor Binding Protein 5; D015850:Interleukin-6; D017451:Receptors, Somatomedin; D013002:Somatomedins; D014409:Tumor Necrosis Factor-alpha; D050822:Cytokine Receptor gp130; D048049:Extracellular Signal-Regulated MAP Kinases