Intestinal Myofibroblasts in Innate Immune Responses of the Intestine

Gastroenterology. 2003 Jun;124(7):1866-78. doi: 10.1016/s0016-5085(03)00403-7.

Abstract

Background & aims: Intestinal myofibroblasts are known to respond to inflammatory signals and may play a role in Crohn's disease-associated fibrosis. However, putative involvement by myofibroblasts in innate immune responses as part of intestinal host defense has not been characterized. We therefore analyzed expression and regulation of toll-like receptors (TLRs) in colonic human myofibroblasts (CCD-18) and primary human colonic myofibroblasts in comparison with human lung myofibroblasts (CCD-37).

Methods: Expression of TLRs (1-10) and NOD 1 and 2 was assessed before and after stimulation with either lipopolysaccharide (LPS) or lipoteichoic acid (LTA) by using a custom microarray, reverse-transcription polymerase chain reaction, Northern blot and Western blot analysis, and immunohistochemistry. Activation of signaling pathways, translocation of p65, and secretion of interleukin (IL)-8 were determined.

Results: Messenger RNAs encoding for TLR1-9, as well as NOD1 and NOD2, were amplified from cultured and primary human intestinal myofibroblasts. After stimulation with LPS or LTA, a 1.5-4.2-fold up-regulation of TLRs (2, 3, 4, 6, 7) and elements of the signaling cascade (MyD88, TIR domain-containing adapter protein [TIRAP]) was observed. CCD-18 and CCD-37 cells expressed TLR 2 and 4 protein, which were located primarily on the cell membrane. Stimulation with LTA or LPS resulted in activation of the mitogen-activated protein kinases pathway, nuclear translocation of p65, and significantly increased IL-8 secretion.

Conclusions: Bacterial components directly activate intestinal myofibroblasts expressing TLRs. These cells may therefore participate in innate immune responses by sensing and responding to bacterial products that have penetrated into the subepithelial compartment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • Colon / cytology
  • Colon / metabolism
  • Fibroblasts / immunology
  • Humans
  • Immunity, Innate*
  • Inflammatory Bowel Diseases / etiology
  • Interleukin-8 / genetics
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / immunology*
  • Lipopolysaccharides / pharmacology
  • Membrane Glycoproteins / genetics*
  • Mitogen-Activated Protein Kinases / physiology
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / analysis
  • Receptors, Cell Surface / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Teichoic Acids / pharmacology
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Toll-Like Receptors

Substances

  • Interleukin-8
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • RNA, Messenger
  • Receptors, Cell Surface
  • TLR2 protein, human
  • Teichoic Acids
  • Toll-Like Receptor 1
  • Toll-Like Receptor 2
  • Toll-Like Receptors
  • lipoteichoic acid
  • Mitogen-Activated Protein Kinases