Proinflammatory cytokines induce crosstalk between colonic epithelial cells and subepithelial myofibroblasts: implication in intestinal fibrosis

J Crohns Colitis. 2013 May;7(4):286-300. doi: 10.1016/j.crohns.2012.04.008. Epub 2012 May 9.


Background and aims: Colonic epithelial cells and adjacent subepithelial myofibroblasts are important counterparts in the pathogenesis of intestinal inflammation and fibrosis. We investigated the possible crosstalk between them, whilst focusing on the mucosal inflammation pathways that potentially trigger intestinal fibrosis.

Methods: We studied the effects of proinflammatory cytokines (IL-1α, TNF-α, IFN-γ) on human colonic epithelial cell lines and the effects of epithelial cell-conditioned media on primary human colonic subepithelial myofibroblasts isolated from normal controls or patients with inflammatory Crohn's disease along with the corresponding 18CO cell line. Readouts included production of TGF-β and TIMP-1, total collagen synthesis, matrix metalloproteinases MMP-2 and MMP-9 and myofibroblast migration/mobility.

Results: Proinflammatory cytokines upregulated TGF-β and TIMP-1 in colonic epithelial cells. Conditioned medium from these epithelial cell cultures induced production of MMP-9 and collagen and inhibited the migration/mobility of subepithelial myofibroblasts. MMP-9 production depended on endothelin receptor A signalling on responding myofibroblasts. Collagen up-regulation was independent of TGF-β, CTGF, TF and endothelin. Subepithelial myofibroblasts isolated from Crohn's disease patients had similar responses to those isolated from normal controls, with the exception of higher basal collagen production.

Conclusions: Our study indicates that colonic epithelial cells may respond to an inflammatory milieu by inducing myofibroblast functions similar to those observed during intestinal fibrosis.

MeSH terms

  • Biomarkers / metabolism
  • Caco-2 Cells
  • Cell Line
  • Cell Migration Assays
  • Cell Movement
  • Collagen / metabolism
  • Colon / metabolism*
  • Colon / pathology
  • Crohn Disease / metabolism
  • Cytokines / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Fibrosis
  • HT29 Cells
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Matrix Metalloproteinase 9 / metabolism
  • Myofibroblasts / metabolism*
  • Myofibroblasts / physiology
  • Receptor, Endothelin A / metabolism
  • Signal Transduction*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transforming Growth Factor beta / metabolism


  • Biomarkers
  • Cytokines
  • Receptor, Endothelin A
  • Tissue Inhibitor of Metalloproteinase-1
  • Transforming Growth Factor beta
  • Collagen
  • Matrix Metalloproteinase 9