Treatment of experimental (Trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-beta1 plasmid: TGF-beta1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor beta2 chain downregulation.

In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor beta1 (pCMV-TGF-beta1) 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 rTGF-beta1 protein does not have this effect. Intranasal pCMV-TGF-beta1 administration leads to the expression of TGF-beta1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-beta1-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)-gamma production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor beta2 (IL-12Rbeta2) chain expression. Coadministration of anti-IL-10 at the time of pCMV-TGF-beta1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFN-gamma secretion. However, anti-IL-10 leads to increased tumor necrosis factor alpha production, especially in established colitis. Taken together, these studies show that TGF-beta1 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-12Rbeta2 chain expression. In addition, TGF-beta1 may also have an inhibitory effect on IFN-gamma transcription.