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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 cytokine production by LP T cells or by LP adherent macrophages from mice with established TNBS colitis (day 12 after induction). Mice were treated with intranasal administration of pCMV-TGF-β1 or pCI control plasmid and intraperitoneal administration of anti–IL-10 mAbs or rat control IgM on day 7. LPMCs were isolated from pooled colon cell population (n ≧ 6), then separated into LP T cells and macrophages. LP T cells were stimulated with anti-CD3ε/anti-CD28 mAb for TGF-β1, IFN-γ, and IL-10 production, and LP macrophages were stimulated with SAC and IFN-γ for IL-12 production. All four cytokines in the supernatant were determined by ELISA in duplicate wells, and SD was within 5%. One experiment representative of three is shown; these data are obtained from the same experiment shown in Fig. 7.
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Figure 9: In vitro cytokine production by LP T cells or by LP adherent macrophages from mice with established TNBS colitis (day 12 after induction). Mice were treated with intranasal administration of pCMV-TGF-β1 or pCI control plasmid and intraperitoneal administration of anti–IL-10 mAbs or rat control IgM on day 7. LPMCs were isolated from pooled colon cell population (n ≧ 6), then separated into LP T cells and macrophages. LP T cells were stimulated with anti-CD3ε/anti-CD28 mAb for TGF-β1, IFN-γ, and IL-10 production, and LP macrophages were stimulated with SAC and IFN-γ for IL-12 production. All four cytokines in the supernatant were determined by ELISA in duplicate wells, and SD was within 5%. One experiment representative of three is shown; these data are obtained from the same experiment shown in Fig. 7.

Mentions: As noted above, concomitant anti–IL-10 administration does not alter the capacity of pCMV-TGF-β plasmid given intranasally to prevent TNBS colitis, but it does diminish the capacity of the plasmid to treat established TNBS colitis. To determine the basis of this difference, we measured cytokine production by stimulated LP cells (in this case, LP T cells or purified adherent cells) extracted from mouse colons 5 d after intranasal plasmid and/or intraperitneal anti–IL-10 administration. As shown in Fig. 9, cells from mice treated with pCMV-TGF-β1 plasmid with and without intraperitoneal anti–IL-10 administration exhibited decreased IFN-γ production. Furthermore, as also shown in Fig. 9, administration of pCMV-TGF-β was again accompanied by downregulated IFN-γ–induced IL-12 production, and this was again reversed by administration of anti–IL-10 but not by administration of control rat IgM. In parallel with the situation obtained during administration of pCMV-TGF-β1 plasmid to mice during induction of TNBS colitis, such administration of the plasmid in established colitis led to increased IL-10 production by LP T cells (Fig. 9), but had little effect on production of IL-10 by LP adherent cells (data not shown).


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 cytokine production by LP T cells or by LP adherent macrophages from mice with established TNBS colitis (day 12 after induction). Mice were treated with intranasal administration of pCMV-TGF-β1 or pCI control plasmid and intraperitoneal administration of anti–IL-10 mAbs or rat control IgM on day 7. LPMCs were isolated from pooled colon cell population (n ≧ 6), then separated into LP T cells and macrophages. LP T cells were stimulated with anti-CD3ε/anti-CD28 mAb for TGF-β1, IFN-γ, and IL-10 production, and LP macrophages were stimulated with SAC and IFN-γ for IL-12 production. All four cytokines in the supernatant were determined by ELISA in duplicate wells, and SD was within 5%. One experiment representative of three is shown; these data are obtained from the same experiment shown in Fig. 7.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC1887715&req=5

Figure 9: In vitro cytokine production by LP T cells or by LP adherent macrophages from mice with established TNBS colitis (day 12 after induction). Mice were treated with intranasal administration of pCMV-TGF-β1 or pCI control plasmid and intraperitoneal administration of anti–IL-10 mAbs or rat control IgM on day 7. LPMCs were isolated from pooled colon cell population (n ≧ 6), then separated into LP T cells and macrophages. LP T cells were stimulated with anti-CD3ε/anti-CD28 mAb for TGF-β1, IFN-γ, and IL-10 production, and LP macrophages were stimulated with SAC and IFN-γ for IL-12 production. All four cytokines in the supernatant were determined by ELISA in duplicate wells, and SD was within 5%. One experiment representative of three is shown; these data are obtained from the same experiment shown in Fig. 7.
Mentions: As noted above, concomitant anti–IL-10 administration does not alter the capacity of pCMV-TGF-β plasmid given intranasally to prevent TNBS colitis, but it does diminish the capacity of the plasmid to treat established TNBS colitis. To determine the basis of this difference, we measured cytokine production by stimulated LP cells (in this case, LP T cells or purified adherent cells) extracted from mouse colons 5 d after intranasal plasmid and/or intraperitneal anti–IL-10 administration. As shown in Fig. 9, cells from mice treated with pCMV-TGF-β1 plasmid with and without intraperitoneal anti–IL-10 administration exhibited decreased IFN-γ production. Furthermore, as also shown in Fig. 9, administration of pCMV-TGF-β was again accompanied by downregulated IFN-γ–induced IL-12 production, and this was again reversed by administration of anti–IL-10 but not by administration of control rat IgM. In parallel with the situation obtained during administration of pCMV-TGF-β1 plasmid to mice during induction of TNBS colitis, such administration of the plasmid in established colitis led to increased IL-10 production by LP T cells (Fig. 9), but had little effect on production of IL-10 by LP adherent cells (data not shown).

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