Blockage of tumor necrosis factor prevents intestinal mucosal inflammation through down-regulation of interleukin-23 secretion.

Tumor necrosis factor (TNF) plays an important part in the pathogenesis of several inflammatory diseases. Its expression is highly increased in inflamed mucosa of inflammatory bowel disease, and anti-TNF treatment appears to improve mucosal inflammation in these patients. However, the role of TNF in the pathogenesis remains to be investigated. In the present study, an experimental colitis was induced by transfer of syngeneic CD45RB(high)CD4(+) T cells into SCID mice. Quantitative analysis of interleukin (IL)-23p19 and IL-17 mRNA was demonstrated to be markedly increased in inflamed colon 4 and 8 weeks after CD45RB(high)CD4(+) T-cell transfer. These SCID recipients were treated i.p. with anti-TNF mAb starting at the beginning (early treatment) or 4 weeks (delayed treatment) after T-cell transfer to investigate the in vivo relevance of TNF to the pathogenesis. The results demonstrated that early treatment with anti-TNF effectively prevented intestinal mucosal inflammation, as evidenced by gradual increase of body weight and absence of diarrhea. Anti-TNF significantly suppressed leukocyte infiltration in the inflamed colon, and down-regulated IFN-gamma, IL-2 and TNF secretion by lamina propria CD4(+) T cells. Interestingly, anti-TNF also significantly decreased expression of IL-23p19 and IL-17 in inflamed colon. Moreover, delayed anti-TNF treatment demonstrated to markedly improve mucosal inflammation. The data suggest that administration of anti-TNF reverses mucosal inflammation via down-regulated pro-inflammatory cytokines, particularly IL-23p19 and IL-17, and decreased leukocyte infiltration in the bowel, thus providing additional relevance of target therapy against TNF.