Epinephrine stimulates IL-6 expression in skeletal muscle and C2C12 myoblasts: role of c-Jun NH2-terminal kinase and histone deacetylase activity

• Published in: American journal of physiology: endocrinology and metabolism Vol. 286; no. 5; pp. E809 - E817
• Main Authors: Frost, Robert A, Nystrom, Gerald J, Lang, Charles H
• Format: Journal Article
• Language: English
• Published: United States 01.05.2004
• Subjects: Animals; Cells, Cultured; Epinephrine - physiology; Histone Deacetylase Inhibitors; Histone Deacetylases - physiology; Interleukin-6 - genetics; Interleukin-6 - metabolism; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides - pharmacology; Male; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - physiology; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - enzymology; Myoblasts, Skeletal - drug effects; Myoblasts, Skeletal - enzymology; Myoblasts, Skeletal - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta - physiology; RNA, Messenger - analysis; Stress, Physiological - physiopathology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00560.2003

Departments of Cellular and Molecular Physiology, and Surgery, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033 Submitted 9 December 2003 ; accepted in final form 6 January 2004 Although an individual's genetic makeup is a major determinant of muscle mass, other influences, such as hormones, cytokines, nutrition, and exercise can also modulate muscle size. IL-6 is an important inflammatory cytokine. Mice that overexpress IL-6 fail to thrive and/or have reduced skeletal muscle mass. The purpose of the present study was to determine whether the stress hormone epinephrine increases inflammatory cytokine expression in skeletal muscle and muscle cells. Infusion of epinephrine in vivo for 2 h increased IL-6 protein (15-fold) and mRNA (40-fold) in skeletal muscle but not in liver. Epinephrine had a similar effect in C 2 C 12 muscle cells, where the hormone increased IL-6 protein and mRNA in a dose- and time-dependent manner. Epinephrine-stimulated IL-6 expression was attenuated by the -adrenergic receptor antagonist phentolamine and completely blocked by either the 1/2 -adrenergic receptor antagonist propranalol or the 2 -antagonist ICI-118551. The transcriptional inhibitor DRB and the synthetic glucocorticoid dexamethasone also blocked epinephrine-induced IL-6. SP-600125 (a JNK inhibitor) and SB-202190 (a p38 MAP kinase inhibitor) completely blocked epinephrine-induced IL-6 synthesis. Endotoxin and epinephrine given together had a synergistic affect on IL-6 mRNA and protein expression. Trichostatin A (a histone deacetylase inhibitor) blocked both endotoxin- and epinephrine-induced IL-6 expression. These data suggest that epinephrine induces IL-6 synthesis in skeletal muscle in vivo and myocytes in vitro. Epinephrine utilizes predominantly the 1/2 -adrenergic receptors to stimulate IL-6 synthesis. Endotoxin and epinephrine synergize to increase IL-6 mRNA expression. Optimal IL-6 synthesis may require both stress kinase and histone deacetylase activity. adrenergic receptors; interleukin-6 Address for reprint requests and other correspondence: R. A. Frost, Dept. of Cellular and Molecular Physiology, Penn State Univ. College of Medicine, Hershey Medical Center: H166, Hershey, PA 17033 (E-mail: rfrost{at}psu.edu ).