Treatment of experimental (Trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-β1 plasmid:: TGF-β1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor β2 chain downregulation

In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor beta 1 (pCMV-TGF-beta 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 rTGF-beta 1 protein does not have this effect. Intranasal pCMV-TGF-beta 1 administration leads to the expression of TGF-beta 1 mRNA ill the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-beta 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)-gamma production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor beta 2 (IL-12R beta 2) chain expression. Coadministration of anti-IL-10 at the time of pCMV-TCF-beta 1 administration prevents the enhancement of IL-10 production and reverses the supression of IL-12 but not IFN-gamma secretion. However, anti-IL-10 leads to increased tumor necrosis factor or production, especially in established colitis. Taken together, these studies show that TGF-P 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 beta 2 chain expression. In addition, TGF-beta 1 may also have an inhibitory effect on IFN-gamma transcription.