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

Abstract

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 (Apc(Min/+); 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 adipocyte-specific cytokine leptin and obesity-associated colon cancer.

Treatment with Anti-Interleukin-6 Receptor Antibody Ameliorates Intestinal Polyposis in <i>Apc</i>^<i>Min/+</i> Mice under High-Fat Diet Conditions

“…The effect of IL-6 signaling in colon epithelial proliferation has been previously demonstrated in a cell line (Fenton et al 2006). And the blockade of IL-6 signaling with the MR16-1 antibody inhibited this proliferation.…”

Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages

“…[41][42][43] Furthermore, several other studies substantiate our finding that IL-6 can directly promote proliferation on colon cancer epithelial cells. 41,[44][45][46][47] To our knowledge, CCL2 has not been previously shown to promote proliferation of colon cancer cells; however, it has been shown to promote invasion in colon cancer epithelial cells 48 and proliferation of a lung cancer cell line. 49 We are also not aware of evidence suggesting a role of IL-1a acting on epithelial cells in colon cancer or other solid tumors to promote malignant behavior.…”

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

“…In addition, the enhanced histological damage could be attributed to upregulation of IL-6, which has been shown to degrade the epithelial barrier and increase cell proliferation. 42 To summarize, the Muc2/IL-10 DKO mouse clearly demonstrates that combined abnormalities in immunoregulatory and epithelial factors greatly accelerate and exacerbate the phenotype of colonic inflammation. In fact, in our facility, the IL-10 À/À mice show no distinct clinical or histological signs of colitis at 5 weeks of age indicating that the mucus barrier offers enough protection under unchallenged conditions.…”