Loss of Functionally Redundant p38 Isoforms in T Cells Enhances Regulatory T Cell Induction

Hayakawa, Morisada; Hayakawa, Hiroko; Petrova, Tsvetana; Ritprajak, Patcharee; Sutavani, Ruhcha V.; Jiménez-Andrade, Guillermina Yanek; Sano, Yasuyo; Choo, Min‐Kyung; Seavitt, John R.; Venigalla, Ram Kumar; Otsu, Kinya; Georgopoulos, Katia; Arthur, J. Simon C.; Park, Jin Mo

doi:10.1074/jbc.m116.764548

Cited by 26 publications

(24 citation statements)

References 48 publications

(63 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We did not observe a change in TGF-β target gene expression by RNA sequencing (RNA-seq) analysis (Supplemental Figure 5), suggesting that Hrd1 might regulate TGF-β signaling in a noncanonical way. In addition, p38 signaling has been reported to associate with TGF-β-mediated conversion of CD4 + CD25 -T cells into Tregs and that loss of p38 redundant isoforms in T cells upregulates FoxP3 expression (43). Similarly, our findings suggest that the signal strength of the p38 signaling pathway is critical for TGF-β-induced FoxP3 expression.…”

Section: Discussionsupporting

confidence: 71%

The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine–induced ER stress response

Melo‐Cardenas

Zhang

et al. 2019

JCI Insight

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 71%

The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine–induced ER stress response

Melo‐Cardenas

Zhang

et al. 2019

JCI Insight

View full text Add to dashboard Cite

“…This signaling pathway also seems to negative regulate the induction of iTregs. P38-deficient T cells showed attenuated MAPK-activated proteinkinase-dependent mTOR signaling after TCR stimulation accompanied by enhanced differentiation into iTregs under appropriate polarizing conditions (34). On the other hand, p38 is also involved in the regulation of IFN-γ expression.…”

Section: Discussionmentioning

confidence: 99%

T Cell-Specific Overexpression of Acid Sphingomyelinase Results in Elevated T Cell Activation and Reduced Parasitemia During Plasmodium yoelii Infection

et al. 2019

View full text Add to dashboard Cite

The enzyme acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and is thereby involved in several cellular processes such as differentiation, proliferation, and apoptosis in different cell types. However, the function of ASM in T cells is still not well characterized. Here, we used T cell-specific ASM overexpressing mice (t-ASM/CD4cre) to clarify the impact of cell-intrinsic ASM activity on T cell function in vitro and in vivo . We showed that t-ASM/CD4cre mice exhibit decreased frequencies of Foxp3 + T regulatory cells (Tregs) within the spleen. Enforced T cell-specific ASM expression resulted in less efficient induction of Tregs and promoted differentiation of CD4 + CD25 − naïve T cells into IFN-γ producing Th1 cells in vitro . Further analysis revealed that ASM-overexpressing T cells from t-ASM/CD4cre mice show elevated T cell receptor (TCR) signaling activity accompanied with increased proliferation upon stimulation in vitro . Plasmodium yoelii infection of t-ASM/CD4cre mice resulted in enhanced T cell activation and was associated with reduced parasitemia in comparison to infected control mice. Hence, our results provide evidence that ASM activity modulates T cell function in vitro and in vivo .

show abstract

“…However, more evidence indicates that inactivation or inhibition of p38 MAPK dampens the suppressive function of induced Tregs (iTregs). For example, the number of Tregs was increased in mice with T cells deficient in p38α and p38β ( 44 ). Inhibition of p38 MAPK with SB203580 significantly abrogated chronic stress-induced differentiation of Foxp3 + iTregs ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

The p38 MAPK Inhibitor SB203580 Abrogates Tumor Necrosis Factor-Induced Proliferative Expansion of Mouse CD4+Foxp3+ Regulatory T Cells

Liu

Chen

et al. 2018

Front. Immunol.

View full text Add to dashboard Cite

There is now compelling evidence that tumor necrosis factor (TNF) preferentially activates and expands CD4+Foxp3+ regulatory T cells (Tregs) through TNF receptor type II (TNFR2). However, it remains unclear which signaling transduction pathway(s) of TNFR2 is required for the stimulation of Tregs. Previously, it was shown that the interaction of TNF–TNFR2 resulted in the activation of a number of signaling pathways, including p38 MAPK, NF-κB, in T cells. We thus examined the role of p38 MAPK and NF-κB in TNF-mediated activation of Tregs, by using specific small molecule inhibitors. The results show that treatment with specific p38 MAPK inhibitor SB203580, rather than NF-κB inhibitors (Sulfasalazine and Bay 11-7082), abrogated TNF-induced expansion of Tregs in vitro. Furthermore, upregulation of TNFR2 and Foxp3 expression in Tregs by TNF was also markedly inhibited by SB203580. The proliferative expansion and the upregulation of TNFR2 expression on Tregs in LPS-treated mice were mediated by TNF–TNFR2 interaction, as shown by our previous study. The expansion of Tregs in LPS-treated mice were also markedly inhibited by in vivo treatment with SB203580. Taken together, our data clearly indicate that the activation of p38 MAPK is attributable to TNF/TNFR2-mediated activation and proliferative expansion of Tregs. Our results also suggest that targeting of p38 MAPK by pharmacological agent may represent a novel strategy to up- or downregulation of Treg activity for therapeutic purposes.

show abstract

Loss of Functionally Redundant p38 Isoforms in T Cells Enhances Regulatory T Cell Induction

Cited by 26 publications

References 48 publications

The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine–induced ER stress response

The E3 ligase Hrd1 stabilizes Tregs by antagonizing inflammatory cytokine–induced ER stress response

T Cell-Specific Overexpression of Acid Sphingomyelinase Results in Elevated T Cell Activation and Reduced Parasitemia During Plasmodium yoelii Infection

The p38 MAPK Inhibitor SB203580 Abrogates Tumor Necrosis Factor-Induced Proliferative Expansion of Mouse CD4+Foxp3+ Regulatory T Cells

Contact Info

Product

Resources

About