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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.

Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W - J. Exp. Med. (2000)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
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.

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In vitro TNF-α production by LP macrophages obtained from mice treated with intranasal administration of pCMV-TGF-β1 and coadministration intraperitoneally of anti–IL-10 mAbs or rat control IgM. Cells were obtained at day 5 during the induction phase (hatched bars) or at day 12 during the established phase (black bars) of TNBS colitis, and were cultured with SAC and IFN-γ for 24 h. Results of one representative experiment of three are shown. ELISA was performed in duplicate wells, and SD was within 5%.
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Figure 10: In vitro TNF-α production by LP macrophages obtained from mice treated with intranasal administration of pCMV-TGF-β1 and coadministration intraperitoneally of anti–IL-10 mAbs or rat control IgM. Cells were obtained at day 5 during the induction phase (hatched bars) or at day 12 during the established phase (black bars) of TNBS colitis, and were cultured with SAC and IFN-γ for 24 h. Results of one representative experiment of three are shown. ELISA was performed in duplicate wells, and SD was within 5%.

Mentions: Finally, as shown in Fig. 10, intranasal pCMV-TGF-β1 administration plus intraperitoneal anti–IL-10 administration led to increased adherent cell TNF-α secretion, which was not seen in the absence of anti–IL-10 administration. Thus, it appears that the ability of anti–IL-10 administration to decrease the effect of intranasal pCMV-TGF-β1 plasmid administration on established TNBS colitis is due to loss of the downregulating effect of IL-10 on TNF-α secretion.


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.

Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W - J. Exp. Med. (2000)

In vitro TNF-α production by LP macrophages obtained from mice treated with intranasal administration of pCMV-TGF-β1 and coadministration intraperitoneally of anti–IL-10 mAbs or rat control IgM. Cells were obtained at day 5 during the induction phase (hatched bars) or at day 12 during the established phase (black bars) of TNBS colitis, and were cultured with SAC and IFN-γ for 24 h. Results of one representative experiment of three are shown. ELISA was performed in duplicate wells, and SD was within 5%.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887715&req=5

Figure 10: In vitro TNF-α production by LP macrophages obtained from mice treated with intranasal administration of pCMV-TGF-β1 and coadministration intraperitoneally of anti–IL-10 mAbs or rat control IgM. Cells were obtained at day 5 during the induction phase (hatched bars) or at day 12 during the established phase (black bars) of TNBS colitis, and were cultured with SAC and IFN-γ for 24 h. Results of one representative experiment of three are shown. ELISA was performed in duplicate wells, and SD was within 5%.
Mentions: Finally, as shown in Fig. 10, intranasal pCMV-TGF-β1 administration plus intraperitoneal anti–IL-10 administration led to increased adherent cell TNF-α secretion, which was not seen in the absence of anti–IL-10 administration. Thus, it appears that the ability of anti–IL-10 administration to decrease the effect of intranasal pCMV-TGF-β1 plasmid administration on established TNBS colitis is due to loss of the downregulating effect of IL-10 on TNF-α secretion.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus