Inhibition of interleukin 6-mediated mitogen-activated... : Hepatology (original) (raw)

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Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line

Park, Joongwon1, 3; Tadlock, Laura2; Gores, Gregory J.1; Patel, Tushar*,2

1Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN

2Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, TX

3Division of Gastroenterology, Chung-ang University Hospital, Seoul, Korea

E-mail: [email protected]

*Address reprint requests to: Division of Gastroenterology, Scott and White Clinic, Texas A&M University System Health Science Center, College of Medicine, 2401 South 31st Street, Temple, TX 76508 fax: 254-724-8276

Received March 22, 1999; accepted August 18, 1999; previously published online December 30, 2003

Abstract

Biliary tract malignancies represent challenges because of the lack of effective therapy and poor prognosis, in part because of the paucity of information regarding the mechanisms regulating their growth. We have recently identified a critical role for the p44/p42 mitogen-activated protein kinase (MAPK) pathway in interleukin 6 (IL-6)-stimulated growth of human cholangiocytes. Although IL-6 is a potential mitogen for cholangiocarcinoma, the role of this cytokine and its intracellular signaling pathways in cholangiocarcinoma growth is unknown. Thus, our aims were to determine the role of IL-6-mediated signaling mechanisms, and in particular the MAPK pathways, in the growth regulation of human cholangiocarcinoma. KMCH-1 cells (malignant cholangiocyte cells) secreted IL-6 constitutively, and increased IL-6 secretion in response to inflammatory cytokines such as tumor necrosis factor α (TNF-α) and IL-1β. Stimulation with IL-6 resulted in proliferation of malignant cholangiocytes. These cells also possessed the IL-6 receptor complex subunits as directly assessed by immunoblot analysis. Furthermore, proliferation was completely inhibited by preincubation with anti-IL-6 neutralizing antibodies, indicating that the proliferative response to IL-6 involved receptor-mediated signaling. Both p38 and p44/p42 MAPKs were constitutively present and active in malignant cholangiocytes, and increased activity of both was observed within 15 minutes of stimulation with IL-6. Selective inhibition of either the p44/p42 MAPK pathway, by PD098059, or of the p38 MAPK pathway, by SB203580, blocked proliferation in response to IL-6. Thus, IL-6 can contribute to the autocrine and/or paracrine growth stimulation of malignant cholangiocytes via activation of either p38 or p44/p42 MAPK signaling pathways.