Prototypical anti-inflammatory cytokine IL-10 prevents loss of IGF-I-induced myogenin protein expression caused by IL-1beta.
Prolonged and excessive inflammation is implicated in resistance to the biological actions of IGF-I and contributes to the pathophysiology of neurodegenerative, metabolic, and muscle-wasting disorders. IL-10 is a critical anti-inflammatory cytokine that restrains inflammatory responses in macrophages and T cells by inhibiting cytokine and chemokine synthesis and reducing expression of their receptors. Here we demonstrate that IL-10 plays a protective role in nonhematopoietic cells by suppressing the ability of exogenous IL-1beta to inhibit IGF-I-induced myogenin and myosin heavy chain expression in myoblasts. This action of IL-10 is not caused by impairment of IL-1beta-induced synthesis of IL-6 or the ability of IL-1beta to activate two members of the MAPK family, ERK1/2 and p38. Instead, this newly defined protective role of IL-10 occurs by specific reversal of IL-1beta activation of the JNK kinase pathway. IL-10 blocks IL-1beta-induced phosphorylation of JNK, but not ERK1/2 or p38, indicating that only the JNK component of the IL-1beta-induced MAPK signaling pathway is targeted by IL-10. This conclusion is supported by the finding that a specific JNK inhibitor acts similarly to IL-10 to restore IGF-I-induced myogenin expression, which is suppressed by IL-1beta. Collectively, these data demonstrate that IL-10 acts in a novel, nonclassical, protective manner in nonhematopoietic cells to inhibit the IL-1beta receptor-induced JNK kinase pathway, resulting in prevention of IGF-I resistance.
Strle
Klemen
K
Laboratory of Integrative Immunophysiology, Integrative Immunology and Behavior Program, Department of Animal Sciences, College of Agricultural, Consumer and Enviromental Sciences, University of Illinois, Urbana, IL 61801, USA.
McCusker
Robert H
RH
Johnson
Rodney W
RW
Zunich
Samantha M
SM
Dantzer
Robert
R
Kelley
Keith W
KW
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D032446:Myoblasts / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018008:Myogenin / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects
D053583:Interleukin-1beta; C503801:Myog protein, mouse; D018008:Myogenin; D016753:Interleukin-10; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3