THE EFFECT OF INTERLEUKIN-6 (IL-6)/gp130 SIGNALLING ON BILIARY EPITHELIAL CELL GROWTH, IN VITRO

doi:10.1006/cyto.1999.0612

Cytokine

Volume 12, Issue 6, June 2000, Pages 727-730

https://doi.org/10.1006/cyto.1999.0612 Get rights and content

Abstract

The effect of IL-6 on the growth of mouse biliary epithelial cells (BEC), in vitro, was tested by comparing BEC obtained IL-6-deficient mice (IL-6^−/−) to wild-type littermate controls (IL-6^+/+), in two different media: simple serum-free media (S-SFM), and complete serum-free media (C-SFM) containing forskolin, which stimulates BEC IL-6 production. In S-SFM, neither IL-6^+/+nor IL-6^−/−BEC constitutively produced IL-6 mRNA or protein, and there was no difference between IL-6^+/+and IL-6^−/−BEC growth. In contrast, when the BEC were maintained in C-SFM, over 48 h, the growth of IL-6^+/+BEC was 40% greater than IL-6^−/−BEC (P<0.006). Enhanced IL-6^+/+BEC growth in C-SFM was associated with induced expression of IL-6 mRNA and IL-6 protein secretion into the medium, upregulation of the IL-6Rα (gp80) and phosphorylation of the signal transducing molecule gp130. In C-SFM, anti-IL-6 neutralizing antibodies blocked enhanced IL-6^+/+BEC growth, whereas exogenous rhIL-6 stimulated retarded growth of IL-6^−/−BEC. Thus, under conditions that mimic an inflammatory or stressful microenvironment in vivo, BEC produce, secrete and respond to IL-6, via upregulation and activation of the IL-6Rα (gp80)/gp130 signaling system in an autocrine/paracrine manner.

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Role of crosstalk between interleukin-6 and transforming growth factor-beta 1 in epithelial-mesenchymal transition and chemoresistance in biliary tract cancer
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Citation Excerpt :
Because IL-6 and TGF-β1 are produced during the inflammatory response,19 it is possible that areas where BTC develops are exposed to these cytokines.14 Previous studies found that IL-6 is elevated in the bile and serum of BTC patients,16,17 and TGF-β1 is markedly increased in inflammatory and obstructive lesions of the bile duct;15,20 furthermore, their receptors are expressed in BTC cells.12,18,21–25 In these previous reports, IL-6 was implicated as a critical growth factor for BTC cells,26 and TGF-β1 was associated with neoplastic transformation.18
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We employed five BTC cell lines (MzChA-1, gemcitabine-resistant MzChA-1, HuCCT-1, KMCH and CCLP-1) to evaluate IL-6/TGF-β1 expression, tumour cell invasion, EMT and chemoresistance to gemcitabine in the presence or absence of recombinant human (rh) IL-6 and TGF-β1. Possible pathways were evaluated with specific pathway inhibitors and small interfering RNA (siRNA). We also used 20 resected specimens from patients with BTC to verify the results in vitro.
IL-6 and TGF-β1 expression was associated with features of malignancy such as EMT and chemoresistance in the four BTC cell lines. Addition of rh IL-6 and TGF-β1 increased endogenous IL-6 and TGF-β1 expression through crosstalk and induced cell invasion, EMT and chemoresistance. Smad4 functioned in this process in a dominant manner, and inhibition by SMAD4 siRNA reduced IL-6 and TGF-β1 expression, blocked invasion, and reversed EMT and chemoresistance in cells exposed to rh IL-6 and TGF-β1 and in gemcitabine-resistant cells. Immunohistochemistry in resected specimens revealed IL6, TGF-β1, N-cadherin and Smad4 staining at the invasion front.
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Primary mouse and human BEC were cultured on collagen gels or collagen-coated plates in complete serum-free medium (C-SFM) as described [10]. The human bile duct cell line, SG231 [11], was cultured as reported [10]. Human SPRR2A cDNA (X53064) was generated by RT-PCR from total RNA from primary human BEC.
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These observations suggest that SPRR2A-related BEC barrier modifications represent a novel, but widely utilized and evolutionarily conserved, response to stress that is worthy of further study.

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^f1: Correspondence to: Dr A. J. Demetris, E1548 BMST, University of Pittsburgh, Pittsburgh, PA 15261, USA; E-mail:[email protected]

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Short CommunicationTHE EFFECT OF INTERLEUKIN-6 (IL-6)/gp130 SIGNALLING ON BILIARY EPITHELIAL CELL GROWTH, IN VITRO

Abstract

Immunobiology

Am J Pathol

J Hepatol

Gastroenterology

Interleukin 6 and its receptor: ten years later

Int Rev Immunol

Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro

Hepatology

Hepatology

Short Communication
THE EFFECT OF INTERLEUKIN-6 (IL-6)/gp130 SIGNALLING ON BILIARY EPITHELIAL CELL GROWTH, IN VITRO