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

Joongwon Park, Laura Tadlock, Gregory James Gores, Tushar C Patel

Research output: Contribution to journalArticle

157 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1128-1133
Number of pages6
JournalHepatology
Volume30
Issue number5
DOIs
StatePublished - 1999

Fingerprint

Cholangiocarcinoma
Mitogen-Activated Protein Kinases
Interleukin-6
Cell Line
Growth
Mitogen-Activated Protein Kinase 1
Interleukin-6 Receptors
Cytokines
Mitogen-Activated Protein Kinase 3
Biliary Tract
p38 Mitogen-Activated Protein Kinases
Neutralizing Antibodies
Interleukin-1
Mitogens
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Hepatology

Cite this

Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. / Park, Joongwon; Tadlock, Laura; Gores, Gregory James; Patel, Tushar C.

In: Hepatology, Vol. 30, No. 5, 1999, p. 1128-1133.

Research output: Contribution to journalArticle

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AB - 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.

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