Treatment of Experimental (Trinitrobenzene Sulfonic Acid) Colitis by Intranasal Administration of Transforming Growth

In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor b 1 (pCMV-TGFb 1) prevents the development of T helper cell type 1 (Th1)mediated experimental colitis induced by the haptenating reagent, 2,4,6-trinitrobenzene sulfonic acid (TNBS). In addition, such plasmid administration abrogates TNBS colitis after it has been established, whereas, in contrast, intraperitoneal administration of rTGFb 1 protein does not have this effect. Intranasal pCMV-TGFb 1 administration leads to the expression of TGFb 1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGFb 1–producing T cells and macrophages in these tissues, and is not associated with the appearances of fibrosis. These cells cause marked suppression of interleukin (IL)-12 and interferon (IFN)g production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor b 2 (IL-12R b 2) chain expression. Coadministration of anti–IL-10 at the time of pCMVTGFb 1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFNg secretion. However, anti–IL-10 leads to increased tumor necrosis factor a production, especially in established colitis. Taken together, these studies show that TGFb 1 inhibition of a Th1-mediated colitis is due to: (a) suppression of IL-12 secretion by IL-10 induction and (b) inhibition of IL-12 signaling via downregulation of IL-12R b 2 chain expression. In addition, TGFb 1 may also have an inhibitory effect on IFNg transcription.