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Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice.

Iijima H, Takahashi I, Kishi D, Kim JK, Kawano S, Hori M, Kiyono H - J. Exp. Med. (1999)

Bottom Line: The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4.Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression.These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

View Article: PubMed Central - PubMed

Affiliation: Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Japan.

ABSTRACT
T cell receptor alpha chain-deficient (TCR-alpha(-/-)) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4(+)betabeta T cells, we treated TCR-alpha(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-alpha(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression. These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

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Cytokine-specific mRNA expression by CD4+ββ T cells in the mucosal compartment of TCR-α−/− mice treated with or without anti–IL-4 mAb. CD4+ββ T cells in the MLNs and colonic LP of TCR-α−/− mice treated with anti–IL-4 mAb (A) or mock Ab (M) were purified by flow cytometry, and cytokine-specific mRNA expression was analyzed by Th1 and Th2 cytokine-specific RT-PCR. The far left column (MW) shows a 1-kb DNA ladder.
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Figure 4: Cytokine-specific mRNA expression by CD4+ββ T cells in the mucosal compartment of TCR-α−/− mice treated with or without anti–IL-4 mAb. CD4+ββ T cells in the MLNs and colonic LP of TCR-α−/− mice treated with anti–IL-4 mAb (A) or mock Ab (M) were purified by flow cytometry, and cytokine-specific mRNA expression was analyzed by Th1 and Th2 cytokine-specific RT-PCR. The far left column (MW) shows a 1-kb DNA ladder.

Mentions: As the development of aberrant CD4+ββ T cells was not affected by treatment with anti–IL-4 mAb (Fig. 3), we next analyzed the cytokine profile of CD4+ββ T cells isolated from TCR-α−/− mice treated with anti–IL-4 mAb or mock Ab. The CD4+ββ T cells were isolated from the colonic LP of TCR-α−/− mice by FACS Vantage™, and the profile of Th1 and Th2 cytokine expression was examined by cytokine-specific RT-PCR. Our previous study showed that CD4+ββ T cells could be considered to be of the Th2 phenotype, since a cytokine-specific ELISPOT assay showed that they produced IL-4 but not Th1 cytokines 10. This pattern of Th2-type cytokine production was also confirmed by cytokine-specific RT-PCR, since CD4+ββ T cells isolated from the colonic LP of mock Ab–treated TCR-α−/− mice expressed mRNA specific for IL-4, IL-5, IL-6, and IL-10, but not for Th1-type cytokines (Fig. 4). Conversely, in the TCR-α−/− mice treated with anti–IL-4 mAb, the pattern of cytokine production was significantly changed; namely, specific messages for Th2-type cytokines such as IL-4, IL-5, and IL-10 were not detected, whereas those for Th1-type cytokines (e.g., IFN-γ) were upregulated (Fig. 4). In addition, the analysis of CD4+ββ T cells isolated from the MLNs of IL-4–specific mAb–treated mice resulted in the alteration of cytokine expression from a dominant Th2 to a Th1 type. The reduction of Th2-type cytokine production and the enhancement of Th1-type cytokine production in mice treated with anti–IL-4 mAb were further confirmed at the protein level through ELISA analysis of secreted Th1 and Th2 cytokines (Fig. 5). Thus, in vitro stimulation of colonic lymphocytes isolated from anti–IL-4 mAb–treated mice with anti-CD3∈ or anti–TCR-β resulted in the decrease of Th2 cytokines (e.g., IL-4 and IL-6) and the increase of IFN-γ synthesis. In contrast, treatment with mock Ab resulted in high levels of Th2 cytokine production. These results demonstrate that a shift from a Th2- to Th1-type response was induced in anti–IL-4 mAb–treated TCR-α−/− mice.


Alteration of interleukin 4 production results in the inhibition of T helper type 2 cell-dominated inflammatory bowel disease in T cell receptor alpha chain-deficient mice.

Iijima H, Takahashi I, Kishi D, Kim JK, Kawano S, Hori M, Kiyono H - J. Exp. Med. (1999)

Cytokine-specific mRNA expression by CD4+ββ T cells in the mucosal compartment of TCR-α−/− mice treated with or without anti–IL-4 mAb. CD4+ββ T cells in the MLNs and colonic LP of TCR-α−/− mice treated with anti–IL-4 mAb (A) or mock Ab (M) were purified by flow cytometry, and cytokine-specific mRNA expression was analyzed by Th1 and Th2 cytokine-specific RT-PCR. The far left column (MW) shows a 1-kb DNA ladder.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195615&req=5

Figure 4: Cytokine-specific mRNA expression by CD4+ββ T cells in the mucosal compartment of TCR-α−/− mice treated with or without anti–IL-4 mAb. CD4+ββ T cells in the MLNs and colonic LP of TCR-α−/− mice treated with anti–IL-4 mAb (A) or mock Ab (M) were purified by flow cytometry, and cytokine-specific mRNA expression was analyzed by Th1 and Th2 cytokine-specific RT-PCR. The far left column (MW) shows a 1-kb DNA ladder.
Mentions: As the development of aberrant CD4+ββ T cells was not affected by treatment with anti–IL-4 mAb (Fig. 3), we next analyzed the cytokine profile of CD4+ββ T cells isolated from TCR-α−/− mice treated with anti–IL-4 mAb or mock Ab. The CD4+ββ T cells were isolated from the colonic LP of TCR-α−/− mice by FACS Vantage™, and the profile of Th1 and Th2 cytokine expression was examined by cytokine-specific RT-PCR. Our previous study showed that CD4+ββ T cells could be considered to be of the Th2 phenotype, since a cytokine-specific ELISPOT assay showed that they produced IL-4 but not Th1 cytokines 10. This pattern of Th2-type cytokine production was also confirmed by cytokine-specific RT-PCR, since CD4+ββ T cells isolated from the colonic LP of mock Ab–treated TCR-α−/− mice expressed mRNA specific for IL-4, IL-5, IL-6, and IL-10, but not for Th1-type cytokines (Fig. 4). Conversely, in the TCR-α−/− mice treated with anti–IL-4 mAb, the pattern of cytokine production was significantly changed; namely, specific messages for Th2-type cytokines such as IL-4, IL-5, and IL-10 were not detected, whereas those for Th1-type cytokines (e.g., IFN-γ) were upregulated (Fig. 4). In addition, the analysis of CD4+ββ T cells isolated from the MLNs of IL-4–specific mAb–treated mice resulted in the alteration of cytokine expression from a dominant Th2 to a Th1 type. The reduction of Th2-type cytokine production and the enhancement of Th1-type cytokine production in mice treated with anti–IL-4 mAb were further confirmed at the protein level through ELISA analysis of secreted Th1 and Th2 cytokines (Fig. 5). Thus, in vitro stimulation of colonic lymphocytes isolated from anti–IL-4 mAb–treated mice with anti-CD3∈ or anti–TCR-β resulted in the decrease of Th2 cytokines (e.g., IL-4 and IL-6) and the increase of IFN-γ synthesis. In contrast, treatment with mock Ab resulted in high levels of Th2 cytokine production. These results demonstrate that a shift from a Th2- to Th1-type response was induced in anti–IL-4 mAb–treated TCR-α−/− mice.

Bottom Line: The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4.Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression.These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

View Article: PubMed Central - PubMed

Affiliation: Department of Mucosal Immunology, Research Institute for Microbial Diseases, Osaka University, Japan.

ABSTRACT
T cell receptor alpha chain-deficient (TCR-alpha(-/-)) mice are known to spontaneously develop inflammatory bowel disease (IBD). The colitis that develops in these mice is associated with increased numbers of T helper cell (Th)2-type CD4(+)TCR-betabeta (CD4(+)betabeta) T cells producing predominantly interleukin (IL)-4. To investigate the role of these Th2-type CD4(+)betabeta T cells, we treated TCR-alpha(-/-) mice with anti-IL-4 monoclonal antibody (mAb). Approximately 60% of TCR-alpha(-/-) mice, including those treated with mock Ab and those left untreated, spontaneously developed IBD. However, anti-IL-4 mAb-treated mice exhibited no clinical or histological signs of IBD, and their levels of mucosal and systemic Ab responses were lower than those of mock Ab-treated mice. Although TCR-alpha(-/-) mice treated with either specific or mock Ab developed CD4(+)betabeta T cells, only those treated with anti-IL-4 mAb showed a decrease in Th2-type cytokine production at the level of mRNA and protein and an increase in interferon gamma-specific expression. These findings suggest that IL-4-producing Th2-type CD4(+)betabeta T cells play a major immunopathological role in the induction of IBD in TCR-alpha(-/-) mice, a role that anti-IL-4 mAb inhibits by causing Th2-type CD4(+)betabeta T cells to shift to the Th1 type.

Show MeSH
Related in: MedlinePlus