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Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.

Bertin S, Lozano-Ruiz B, Bachiller V, García-Martínez I, Herdman S, Zapater P, Francés R, Such J, Lee J, Raz E, González-Navajas JM - Mucosal Immunol (2014)

Bottom Line: DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive.In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation.DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.

ABSTRACT
Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-γ production, as well as a marked decrease in survival, interleukin- 17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-)/Dusp6(-/-) double-knockout mice. Il10(-/-)/Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.

No MeSH data available.


Related in: MedlinePlus

ERK inhibition ameliorates colitis in Il10−/−/Dusp6−/−mice(a) H&E staining of Il10−/−/Dusp6−/− mice treated with the MEK1/2 inhibitor PD0325901 (PD) or vehicle five times a week for a total of 10 weeks. Representative micrographs are shown (magnification ×100) (n=6 mice per group). (b) Quantitative measurement of crypt length and cellular infiltration in vehicle-treated or PD-treated mice. (c) Cytokine levels in colonic explant supernatants after 24 hours of culture. Represented values are normalized to milligrams of cultured colonic tissue. Data represent pooled results from two independent experiments with at least 4 mice per group (b–c). Error bars represent standard deviation. n.s: not significant, *P<0.05, **P<0.01
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Figure 6: ERK inhibition ameliorates colitis in Il10−/−/Dusp6−/−mice(a) H&E staining of Il10−/−/Dusp6−/− mice treated with the MEK1/2 inhibitor PD0325901 (PD) or vehicle five times a week for a total of 10 weeks. Representative micrographs are shown (magnification ×100) (n=6 mice per group). (b) Quantitative measurement of crypt length and cellular infiltration in vehicle-treated or PD-treated mice. (c) Cytokine levels in colonic explant supernatants after 24 hours of culture. Represented values are normalized to milligrams of cultured colonic tissue. Data represent pooled results from two independent experiments with at least 4 mice per group (b–c). Error bars represent standard deviation. n.s: not significant, *P<0.05, **P<0.01

Mentions: Our data showing that CD4+ T cells from Dusp6−/− and Il10−/−/Dusp6−/− mice had increased levels of phosphorylated ERK1/2 as well as superior IFN-γ production, together with previous data showing that ERK1/2 promotes colitis by inducing an exacerbated IFN-γ response10, suggested a potential ERK1/2-dependent mechanism driving the pathogenesis of colitis in Il10−/−/Dusp6−/− mice. Since colitis in Il10−/−/Dusp6−/− mice was detected by 10 weeks of age, we administered the ERK inhibitor to 5 week-old Il10−/−/Dusp6−/− mice five times a week for a period of 10 weeks. Vehicle-treated mice developed severe colonic inflammation by the age of 15 weeks, whereas PD treatment significantly reduced the severity of colitis as shown by the lower degree of epithelial crypt hyperplasia and inflammatory cell infiltration into the lamina propria (Figure 6a–b). In addition, ex vivo colonic explants from PD-treated Il10−/−/Dusp6−/− mice also released lower amounts of IFN-γ and TNF-α than vehicle-treated mice (Figure 6c).


Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.

Bertin S, Lozano-Ruiz B, Bachiller V, García-Martínez I, Herdman S, Zapater P, Francés R, Such J, Lee J, Raz E, González-Navajas JM - Mucosal Immunol (2014)

ERK inhibition ameliorates colitis in Il10−/−/Dusp6−/−mice(a) H&E staining of Il10−/−/Dusp6−/− mice treated with the MEK1/2 inhibitor PD0325901 (PD) or vehicle five times a week for a total of 10 weeks. Representative micrographs are shown (magnification ×100) (n=6 mice per group). (b) Quantitative measurement of crypt length and cellular infiltration in vehicle-treated or PD-treated mice. (c) Cytokine levels in colonic explant supernatants after 24 hours of culture. Represented values are normalized to milligrams of cultured colonic tissue. Data represent pooled results from two independent experiments with at least 4 mice per group (b–c). Error bars represent standard deviation. n.s: not significant, *P<0.05, **P<0.01
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Related In: Results  -  Collection

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Figure 6: ERK inhibition ameliorates colitis in Il10−/−/Dusp6−/−mice(a) H&E staining of Il10−/−/Dusp6−/− mice treated with the MEK1/2 inhibitor PD0325901 (PD) or vehicle five times a week for a total of 10 weeks. Representative micrographs are shown (magnification ×100) (n=6 mice per group). (b) Quantitative measurement of crypt length and cellular infiltration in vehicle-treated or PD-treated mice. (c) Cytokine levels in colonic explant supernatants after 24 hours of culture. Represented values are normalized to milligrams of cultured colonic tissue. Data represent pooled results from two independent experiments with at least 4 mice per group (b–c). Error bars represent standard deviation. n.s: not significant, *P<0.05, **P<0.01
Mentions: Our data showing that CD4+ T cells from Dusp6−/− and Il10−/−/Dusp6−/− mice had increased levels of phosphorylated ERK1/2 as well as superior IFN-γ production, together with previous data showing that ERK1/2 promotes colitis by inducing an exacerbated IFN-γ response10, suggested a potential ERK1/2-dependent mechanism driving the pathogenesis of colitis in Il10−/−/Dusp6−/− mice. Since colitis in Il10−/−/Dusp6−/− mice was detected by 10 weeks of age, we administered the ERK inhibitor to 5 week-old Il10−/−/Dusp6−/− mice five times a week for a period of 10 weeks. Vehicle-treated mice developed severe colonic inflammation by the age of 15 weeks, whereas PD treatment significantly reduced the severity of colitis as shown by the lower degree of epithelial crypt hyperplasia and inflammatory cell infiltration into the lamina propria (Figure 6a–b). In addition, ex vivo colonic explants from PD-treated Il10−/−/Dusp6−/− mice also released lower amounts of IFN-γ and TNF-α than vehicle-treated mice (Figure 6c).

Bottom Line: DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive.In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation.DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.

View Article: PubMed Central - PubMed

Affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.

ABSTRACT
Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-γ production, as well as a marked decrease in survival, interleukin- 17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-)/Dusp6(-/-) double-knockout mice. Il10(-/-)/Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.

No MeSH data available.


Related in: MedlinePlus