Journal Article

Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (<sup>Min/+</sup>) colon epithelial cell line

Jenifer I. Fenton, Stephen D. Hursting, Susan N. Perkins and Norman G. Hord

in Carcinogenesis

Volume 27, issue 7, pages 1507-1515
Published in print July 2006 | ISSN: 0143-3334
Published online April 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl018
Interleukin-6 production induced by leptin treatment promotes cell proliferation in an Apc (Min/+) colon epithelial cell line

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Increased visceral adipose tissue results in elevated plasma leptin, which are associated with increased risk of a number of obesity-related cancers. However, research is contradictory regarding the role of elevated plasma leptin in colon cancer risk. Having established that leptin induced proliferation in a murine model of preneoplastic (ApcMin/+; IMCE) colon epithelial cells but not normal (Apc+/+; YAMC) cells, we hypothesized that the leptin-associated IMCE cell proliferation was a result of autocrine interleukin-6 (IL-6) production and ensuing IL-6 receptor (IL-6R) signaling. Here we show, for the first time, that leptin induces elevated IL-6 production in IMCE cells but not in YAMC cells. IL-6 treatment induced cell proliferation in IMCE cells, but not in YAMC cells, in a concentration-dependent manner from 0.1 to 100 ng/ml (P < 0.05). Interleukin-6-induced IMCE cell proliferation was blocked by the addition of a neutralizing anti-IL-6R antibody. In addition, leptin-induced IMCE cell proliferation was blocked by the addition of an anti-IL-6R neutralizing antibody. Further, we elucidate a novel mechanism by which leptin activates TACE/ADAM17-associated IL-6R shedding and trans-IL-6 signaling in IMCE by induction of IL-6 production. IL-6 treatment of IMCE cells was associated with STAT3, ERK, p38, MEK and JAK2 activation and associated STAT3 nuclear activation and translocation. These data implicate leptin-induced IL-6 production, signaling and subsequent STAT3 activation as early events promoting the survival/proliferation of colon epithelial preneoplastic cells. The elucidation of the leptin-initiated mechanism of preneoplastic cell proliferation establishes a biologically plausible link between the adipoctye-specific cytokine leptin and obesity-associated colon cancer.

Keywords: APC, adenomatous polyposis coli; IBD, inflammatory bowel disease; IL-6, Interleukin-6; sIL-6R, soluble form of the IL-6 receptor; sgp130R, soluble gp130 receptor; STAT3, signal transducer and activator of transcription 3; TACE, tumor necrosis factor-converting enzyme

Journal Article.  6061 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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