Original Article
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World J Gastroenterol. Jan 14, 2011; 17(2): 151-163
Published online Jan 14, 2011. doi: 10.3748/wjg.v17.i2.151
Connective tissue growth factor reacts as an IL-6/STAT3-regulated hepatic negative acute phase protein
Olav A Gressner, Ieva Peredniene, Axel M Gressner
Olav A Gressner, Ieva Peredniene, Axel M Gressner, Institute of Clinical Chemistry and Pathobiochemistry, Central Laboratory, RWTH-University Hospital, 52074 Aachen, Germany
Olav A Gressner, Wisplinghoff Medical Laboratories, Classen-Kappelmann-Str. 24, 50931 Cologne, Germany
Ieva Peredniene, Synlab Lab Services, Gubener Str. 39, 86156 Augsburg, Germany
Author contributions: All authors contributed equally to this work; all authors designed the research, analyzed the data and wrote the paper; Peredniene I and Gressner OA performed research.
Correspondence to: Axel M Gressner, Professor Emeritus of the Institute of Clinical Chemistry and Pathobiochemistry, RWTH-University, Lutherweg 2, 52074 Aachen, Germany. gressner@t-online.de
Telephone: +49-2405-4996968 Fax: +49-241-7014300
Received: August 30, 2010
Revised: October 19, 2010
Accepted: October 26, 2010
Published online: January 14, 2011
Abstract

AIM: To investigate the mechanisms involved in a possible modulator role of interleukin (IL)-6 signalling on CYR61-CTGF-NOV (CCN) 2/connective tissue growth factor (CTGF) expression in hepatocytes (PC) and to look for a relation between serum concentrations of these two parameters in patients with acute inflammation.

METHODS: Expression of CCN2/CTGF, p-STAT3, p-Smad3/1 and p-Smad2 was examined in primary freshly isolated rat or cryo-preserved human PC exposed to various stimuli by Western blotting, electrophoretic mobility shift assay (EMSA), reporter-gene-assays and reverse-transcriptase polymerase chain reaction.

RESULTS: IL-6 strongly down-regulated CCN2/CTGF protein and mRNA expression in PC, enhanceable by extracellular presence of the soluble IL-6 receptor gp80, and supported by an inverse relation between IL-6 and CCN2/CTGF concentrations in patients’ sera. The inhibition of TGFβ1 driven CCN2/CTGF expression by IL-6 did not involve a modulation of Smad2 (and Smad1/3) signalling. However, the STAT3 SH2 domain binding peptide, a selective inhibitor of STAT3 DNA binding activity, counteracted the inhibitory effect of IL-6 on CCN2/CTGF expression much more pronounced than pyrrolidine-dithiocarbamate, an inhibitor primarily of STAT3 phosphorylation. An EMSA confirmed STAT3 binding to the proposed proximal STAT binding site in the CCN2/CTGF promoter.

CONCLUSION: CCN2/CTGF is identified as a hepatocellular negative acute phase protein which is down-regulated by IL-6 via the STAT3 pathway through interaction on the DNA binding level.

Keywords: Hepatocytes; Interleukin-6; Connective tissue growth factor; STAT3; Liver fibrosis; Acute phase reaction