Abstract
Stricture formation in Crohn's disease occurs as a result of persistent fibroblast activation. Chronic inflammation seen in patients with Crohn's disease leads to enhanced adhesion molecule expression in fibroblasts. Stress-activated mitogen-activated protein kinases are critical signaling pathways that control expression of intracellular adhesion molecule-1 (ICAM-1) in inflammation. The purpose of this study was to investigate the involvement of stress-activated mitogen-activated protein kinases in the regulation of ICAM-1 expression by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in serosal fibroblasts isolated from patients with Crohn's disease. Fibroblasts were isolated from serosal biopsies of strictures in patients with Crohn's disease and normal colon in patients with colorectal carcinoma. Cell surface and whole cell ICAM-1 expression were evaluated by flow cytometry and Western blot analysis, respectively. Cells were stimulated with TNF-alpha and IL-1beta. To determine the mitogen-activated protein kinase signaling pathway required for ICAM-1 induction, cells were pretreated with inhibitors to Jun N-terminal kinase, p38 kinase, and p42/44 kinase. Baseline ICAM-1 expression was higher (p < 0.001) in fibroblasts isolated from strictures in patients with Crohn's disease (3.2 +/- 0.3) as compared with nonstrictured Crohn's fibroblasts (2.1 +/- 0.3) and control fibroblasts (1.6 +/- 0.1). TNF-alpha and IL-1beta increased ICAM-1 expression in both control and Crohn's disease. Pretreatment of fibroblasts with the Jun N-terminal kinase inhibitor dimethylaminopurine abolished TNF-alpha- and IL-1beta-stimulated ICAM-1 expression. Serosal fibroblasts isolated from strictures of patients with Crohn's disease demonstrate enhanced expression of ICAM-1. TNF-alpha and IL-1beta upregulate ICAM-1 expression in serosal fibroblasts through a Jun N-terminal kinase signaling pathway. Specific inhibition of inflammatory signaling pathways could provide novel therapeutic targets for treatment of Crohn's disease.
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