Cytokine-hormone interactions: tumor necrosis factor alpha impairs biologic activity and downstream activation signals of the insulin-like growth factor I receptor in myoblasts.
TNFalpha is elevated following damage to skeletal muscle. Here we provide evidence that TNFalpha acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNFalpha inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C(2)C(12) murine myoblasts, where as little as 0.01 ng/ml TNFalpha significantly inhibits protein synthesis induced by IGF-I. TNFalpha also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNFalpha of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNFalpha. Although IGF-I induces an approximately 19-fold induction in tyrosine phosphorylation of the beta-chains of its receptor, TNFalpha does not inhibit this autophosphorylation. Instead, TNFalpha significantly reduces by approximately 50% IGF-I-stimulated tyrosine phosphorylation of two of the major downstream receptor docking molecules, insulin receptor substrate (IRS)-1 and IRS-2. These results establish that low picogram concentrations of TNFalpha acts on both porcine and murine myoblasts to impair tyrosine phosphorylation of both IRS-1 and IRS-2, but not the receptor itself. These data are consistent with the notion that very low physiological concentrations of TNFalpha interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.
Broussard
Suzanne R
SR
Laboratory of Immunophysiology, Department of Animal Sciences and Pathology, College of Medicine, University of Illinois at Urbana-Champaign, 207 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, IL 61801, USA. broussar@uiuc.edu
McCusker
Robert H
RH
Novakofski
Jan E
JE
Strle
Klemen
K
Shen
Wen Hong
WH
Johnson
Rodney W
RW
Freund
Gregory G
GG
Dantzer
Robert
R
Kelley
Keith W
KW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018008:Myogenin / Q000096:biosynthesis; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018008:Myogenin; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D017526:Receptor, IGF Type 1