The neutrophil/Th1 lymphocyte balance and the therapeutic effect of granulocyte colony-stimulating factor in TNBS-induced colitis of rat strains.

摘要

Intramucosal neutrophil infiltration is related to the activity of ulcerative colitis, and Th1 immunity is responsible for the onset of Crohn's disease. We examined the therapeutic effects of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in the two types of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of five rat strains. SD and DA rats showed much lower mRNA expression levels of endogenous G-CSF in lipopolysaccharide (LPS)-stimulated splenocytes than did Lewis, F344, and BN rats. On day 7 after anal instillation of TNBS, SD and DA rats demonstrated massive lymphocyte infiltration with an interferon-gamma (IFN-gamma) mRNA upregulation, whereas Lewis, F344, and BN rats showed an intense submucosal neutrophil accumulation with high tumor necrosis factor-alpha (TNF-alpha) mRNA levels. A 5-day course of rHuG-CSF pretreatment (250 microg/kg/day, s.c.) reduced the elevated levels of both cytokines. The treatment improved the survival rate of DA and reduced the degree of body weight loss of SD, while not significantly influencing the wasting disease of other strains. Interleukin-10 (IL-10) mRNA levels were highly upregulated by rHuG-CSF treatment on day 1 in the neutrophil-dominant lesions of F344 but not in the Th1-type lesions of SD, and IL-12p35 mRNA levels were downregulated in both. A supply of G-CSF prevents the onset of Th1-type TNBS colitis and does not deteriorate neutrophil-dominant chronic colitis in hosts showing higher expression of endogenous G-CSF.