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Potential role of protease-activated receptor-2-stimulated activation of cytosolic phospholipase A2 in intestinal myofibroblast proliferation: Implications for stricture formation in Crohn´s disease
University of Kalmar, School of Pure and Applied Natural Sciences.
University of Kalmar, School of Pure and Applied Natural Sciences.
2009 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 3, no 1, p. 15-24Article in journal (Refereed) Published
Abstract [en]

Background and aims

Myofibroblast hyperplasia contributes to muscularis mucosae thickening and stricture formation in Crohn's disease (CD). Protease-activated receptor-2 (PAR-2) and cytosolic phospholipase A2 (cPLA2) are known regulators of cell growth, but their significance in intestinal myofibroblast proliferation remain to be elucidated. The principle aims of the present study were to investigate if PAR-2 is expressed in the expanded muscularis mucosa in ileal CD specimens, if inflammatory cytokines may stimulate PAR-2 expression in intestinal myofibroblasts, and if PAR-2 and cPLA2 may regulate intestinal myofibroblast growth.

Methods

Immunohistochemistry was used for detection of PAR-2 in ileal CD specimens. Studies on PAR-2 expression, PLA2 activation and cell growth were performed in a human intestinal myofibroblast cell line, CCD-18Co. PAR-2 expression was investigated by RT-PCR and immunocytochemistry. PLA2 activity was analyzed by quantification of released 14C-arachidonic acid (14C-AA). Cell growth was examined by 3H-thymidine incorporation and cell counting.

Results

The thickened muscularis mucosae of the CD specimens showed strong PAR-2 expression. In cultured myofibroblasts, tumor necrosis factor-α (TNF-α) up-regulated PAR-2 mRNA and protein, and potentiated PAR-2-stimulated 14C-AA release by two known PAR-2 activators, trypsin and SLIGRL-NH2. The release of 14C-AA was dependent on cPLA2. Trypsin stimulated the proliferation of serum-starved cells, and inhibition of cPLA2 reduced normal cell growth and abolished the growth-promoting effect of trypsin.

Conclusions

The results suggest that PAR-2-mediated cPLA2 activation might be of importance in intestinal myofibroblast proliferation. The results also point to the possibility that PAR-2 up-regulation by inflammatory cytokines, like TNF-α, may modulate this effect.

 

 

 

 

 

Place, publisher, year, edition, pages
2009. Vol. 3, no 1, p. 15-24
Keywords [en]
Crohn's disease, Intestinal myofibroblasts, Phospholipase A2, Protease-activated receptor-2, Tumor necrosis factor-α
National Category
Medical and Health Sciences
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-1967DOI: 10.1016/j.crohns.2008.10.002OAI: oai:DiVA.org:lnu-1967DiVA, id: diva2:309015
Conference
10th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases, Montreal, CANADA,SEP 16-19, 2007
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2017-12-12Bibliographically approved

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Christerson, UlrikaGustafson-Svärd, Christina

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