Original Article

Treatment of Experimental (Trinitrobenzene Sulfonic Acid) Colitis by Intranasal Administration of Transforming Growth Factor (TGF)-ß1 Plasmid: TGF-ß1–mediated Suppression of T Helper Cell Type 1 Response Occurs by Interleukin (IL)-10 Induction and IL-12 Receptor ß2 Chain Downregulation

Correspondence to: Warren Strober, Bldg. 10, Rm. 11N238, 10 Center Dr., Bethesda, MD 20892. Tel:301-496-6810 Fax:301-402-2240 E-mail:wstrober{at}niaid.nih.gov.

In this study, we show that a single intranasal dose of a plasmid encoding active transforming growth factor ß1 (pCMV-TGF-ß1) 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-ß1 protein does not have this effect. Intranasal pCMV-TGF-ß1 administration leads to the expression of TGF-ß1 mRNA in the intestinal lamina propria and spleen for 2 wk, as well as the appearance of TGF-ß1–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)- production and enhancement of IL-10 production; in addition, they inhibit IL-12 receptor ß2 (IL-12Rß2) chain expression. Coadministration of anti–IL-10 at the time of pCMV-TGF-ß1 administration prevents the enhancement of IL-10 production and reverses the suppression of IL-12 but not IFN- secretion. However, anti–IL-10 leads to increased tumor necrosis factor production, especially in established colitis. Taken together, these studies show that TGF-ß1 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-12Rß2 chain expression. In addition, TGF-ß1 may also have an inhibitory effect on IFN- transcription.

Key Words: delivery, hapten, interferon , tumor necrosis factor , ß-galactosidase

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