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Endocrinology Vol. 140, No. 8 3562-3572
Copyright © 1999 by The Endocrine Society

ARTICLES

Intracellular Signaling in Rat Cultured Vascular Smooth Muscle Cells: Roles of Nuclear Factor-{kappa}B and p38 Mitogen-Activated Protein Kinase on Tumor Necrosis Factor-{alpha} Production1

Tadashi Yamakawa, Satoru Eguchi, Takeshi Matsumoto, Yuko Yamakawa, Kotaro Numaguchi, Ichiro Miyata, Cherilynn M. Reynolds, Evangeline D. Motley and Tadashi Inagami

Department of Biochemistry, Vanderbilt University School of Medicine (T.Y., S.E., T.M., T.K., Y.Y., K.N., T.I.), Nashville, Tennessee 37232; and the Department of Anatomy and Physiology, Meharry Medical College (C.M.R., E.D.M.), Nashville, Tennessee 37208

Address all correspondence and requests for reprints to: Tadashi Inagami, Ph.D., Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232. E-mail: inagamit{at}ctrvax.vanderbilt.edu

Lipopolysaccharide (LPS) is responsible for initiating host responses leading to septic shock, and tumor necrosis factor-{alpha} (TNF{alpha}) is thought to be its primary mediator. In addition, TNF{alpha} is one of the major components of the pathogenesis of insulin resistance in various conditions. It has been shown that LPS induced TNF{alpha} production in rat vascular smooth muscle cells (VSMC). However, little is known about the signaling pathway by which VSMC in culture produce TNF{alpha}. We investigated the possible signaling components involved in this pathway. LPS elicited phosphorylation of p42/44 mitogen-activated protein kinase (MAPK) and p38 MAPK, degradation of inhibitor of {kappa}B (I{kappa}B), and an increase in nuclear binding activity of activating protein-1 and nuclear factor-{kappa}B (NF-{kappa}B). Different types of NF-{kappa}B inhibitors, pyrrolidine dithiocarbamate and MG132, which specifically abolished I{kappa}B degradation and subsequent NF-{kappa}B activation by LPS, suppressed TNF{alpha} secretion from VSMC. Although PD98059, a specific MAPK kinase inhibitor and SB203580, a specific p38 MAPK inhibitor, had no effect on NF-{kappa}B activity, SB203580 suppressed TNF{alpha} secretion; however, PD98059 did not. A cotransfection assay showed that transfection of dominant negative I{kappa}B or pretreatment with SB203580 suppressed the TNF{alpha} gene promotor-dependent transcription. TNF{alpha} messenger RNA expression induced by LPS was inhibited by pyrrolidine dithiocarbamate, MG132, and SB203580, but not by PD98059. These observations indicate that TNF{alpha} production in VSMC is stimulated by LPS, and its transcription and translation are dependent on NF-{kappa}B activation through proteasome-mediated I{kappa}B degradation. It is likely that p38 MAPK may play a critical role in regulating transcription of the TNF{alpha} gene in VSMC, unlike in other cell lines.




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