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J. Biol. Chem., Vol. 283, Issue 34, 23224-23234, August 22, 2008

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Inhibition of Myoblast Differentiation by Tumor Necrosis Factor Is Mediated by c-Jun N-terminal Kinase 1 and Leukemia Inhibitory Factor^*

From the Department of Biochemistry, Rappaport Institute for Research in the Medical Sciences, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel

The proinflammatory cytokine, TNF plays a major role in muscle wasting occurring in chronic diseases and muscular dystrophies. Among its other functions, TNF perturbs muscle regeneration by preventing satellite cell differentiation. In the present study, the role of c-Jun N-terminal kinase (JNK), a mediator of TNF, was investigated in differentiating myoblast cell lines. Addition of TNF to C2 myoblasts induced immediate and delayed phases of JNK activity. The delayed phase is associated with myoblast proliferation. Inhibition of JNK activity prevented proliferation and restored differentiation to TNF-treated myoblasts. Studies with cell lines expressing MyoD:ER chimera and lacking JNK1 or JNK2 genes indicate that JNK1 activity mediates the effects of TNF on myoblast proliferation and differentiation. TNF does not induce proliferation or inhibit differentiation of JNK1-null myoblasts. However, differentiation of JNK1-null myoblasts is inhibited when they are grown in conditioned medium derived from cell lines affected by TNF. We investigated the induced synthesis of several candidate growth factors and cytokines following treatment with TNF. Expression of IL-6 and leukemia inhibitory factor (LIF) was induced by TNF in wild-type and JNK2-null myoblasts. However, LIF expression was not induced by TNF in JNK1-null myoblasts. Addition of LIF to the growth medium of JNK1-null myoblasts prevented their differentiation. Moreover, LIF-neutralizing antibodies added to the medium of C2 myoblasts prevented inhibition of differentiation mediated by TNF. Hence, TNF promotes myoblast proliferation through JNK1 and prevents myoblast differentiation through JNK1-mediated secretion of LIF.

Received for publication, February 21, 2008 , and in revised form, May 26, 2008.

^* This work was supported in part by a grant (to E. B.) from the Israel Science Foundation, by a grant from the Israel Cancer Association (the Todores Moshe & Rachel Dziencielki, & Jacob & Zilpa Bass research fund) (to E. B.), and by funds from the Rappaport Foundation for Medical Research and the Foundation for the Promotion of Research in the Technion, Israel Institute of Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ To whom correspondence should be addressed: PO Box 9649, Haifa 31096, Israel. Tel.: 972-4-8295-287; Fax: 972-4-8553-299; E mail: bengal{at}tx.technion.ac.il.

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