Interleukin-6 Production Induced by Leptin Treatment Promotes Cell Proliferation in an Apc (Min/+) Colon Epithelial Cell Line

Carcinogenesis. 2006 Jul;27(7):1507-15. doi: 10.1093/carcin/bgl018. Epub 2006 Apr 5.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADAM Proteins / drug effects
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Proliferation / drug effects
  • Colon / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / drug effects
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Genes, APC
  • Interleukin-6 / metabolism*
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / metabolism
  • Janus Kinase 2
  • Leptin / pharmacology*
  • Mice
  • Mice, Transgenic
  • Obesity / complications
  • Obesity / physiopathology
  • Precancerous Conditions / complications
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism*
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Protein-Tyrosine Kinases / drug effects
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Interleukin-6 / metabolism
  • Receptors, Leptin
  • STAT3 Transcription Factor / drug effects
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Interleukin-6
  • Leptin
  • Proto-Oncogene Proteins
  • Receptors, Interleukin-6
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • leptin receptor, mouse
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • ADAM Proteins
  • ADAM17 Protein
  • Adam17 protein, mouse