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

Abstract

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.

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

“…Similar to TNFR1 and TNFR2 activation may result in induction of the c-Jun N-terminal kinase (JNK) (Jupp et al, 2001) and the p38 MAPK pathway (Inoue et al, 2015;He et al, 2018). Interestingly, recently mitochondrial aminopeptidase P3 (APP3, also known as XPNPEP3) was identified as a novel component of the TNFR2 signal complex, which regulates TNF-TNFR2-dependent phosphorylation of JNK (Inoue et al, 2015).…”

“…The authors describe that APP3 is released from mitochondria in a TNF-defendant way in the absence of mitochondrial outer membrane permeabilization (MOMP) and suggest that APP3 exerts an anti-apoptotic function (Inoue et al, 2015). Interestingly, it was shown that TNFR2 ligation enhances cell proliferation through the non-canonical NFκB pathway in human regulatory T cells (Tregs) (Wang et al, 2018), whereas in mouse Tregs activation of p38 MAPK was important for TNFR2-induced proliferation (He et al, 2018). Furthermore, TNFR2 promotes phosphatidylinositol 3kinase (PI3K)-dependent phosphorylation of the protein kinase PKB/Akt via a yet unknown mechanism (Marchetti et al, 2004;Fischer et al, 2011b).…”

Integrated intra- and intercellular signaling knowledge for multicellular omics analysis

“…We found a 30% increase in the amount of ligand-receptor and ligand-adhesion interactions between myofibroblasts and Treg in UC versus healthy, even though the number of connections is similar in both conditions. In an analysis of downstream signaling in Treg cells we found pathways known to downregulate the pro-inflammatory function of Treg cells to be active in healthy state, including the MAPK 28 , TLR2 29 and TLR7 30 pathways ( Supplementary Table S11). In contrast, the pro-inflammatory TLR4 31 and TLR3 pathways 32 were upregulated in UC.…”

CD28 costimulatory domain protects against tonic signaling-induced functional impairment in CAR-Tregs

“…Notably, the 4-1BB CSD induced much stronger activation of the ERK1/2 MAPK pathway than did the CD28 CSD. The p38-MAPK signaling pathway was found to be instrumental in TNFR2-driven Treg proliferation (He et al, 2018) and in the transduction of 4-1BB-induced activation in CD8+ T cells (Menk et al, 2018). However, our study is the first to show a link between 4-1BB-induced Treg proliferation and MAPK activation.…”