Intestinal myofibroblasts in innate immune responses of the intestine

Jan Michel Otte, Ian M. Rosenberg, Daniel K. Podolsky

Research output: Contribution to journalArticle

179 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1866-1878
Number of pages13
JournalGastroenterology
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2003

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Myofibroblasts
Innate Immunity
Intestines
Lipopolysaccharides
Toll-Like Receptor 2
Toll-Like Receptors
Interleukin-8
Toll-Like Receptor 10
Toll-Like Receptor 1
Toll-Like Receptor 3
Toll-Like Receptor 4
Mitogen-Activated Protein Kinases
Crohn Disease
Northern Blotting
Reverse Transcription
Proteins
Fibrosis
Up-Regulation
Western Blotting
Immunohistochemistry

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Intestinal myofibroblasts in innate immune responses of the intestine. / Otte, Jan Michel; Rosenberg, Ian M.; Podolsky, Daniel K.

In: Gastroenterology, Vol. 124, No. 7, 01.07.2003, p. 1866-1878.

Research output: Contribution to journalArticle

Otte, Jan Michel ; Rosenberg, Ian M. ; Podolsky, Daniel K. / Intestinal myofibroblasts in innate immune responses of the intestine. In: Gastroenterology. 2003 ; Vol. 124, No. 7. pp. 1866-1878.
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AB - 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.

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