MEKK3 Regulates IFN-γ Production in T Cells through the Rac1/2-Dependent MAPK Cascades

Abstract

MEKK3 is a conserved Ser/Thr protein kinase belonging to the MAPK kinase kinase (MAP3K) family. MEKK3 is constitutively expressed in T cells, but its function in T cell immunity has not been fully elucidated. Using Mekk3 T cell conditional knockout (T-cKO) mice, we show that MEKK3 is required for T cell immunity in vivo. Mekk3 T-cKO mice had reduced T cell response to bacterial infection and were defective in clearing bacterial infections. The Ag-induced cytokine production, especially IFN-γ production, was impaired in Mekk3-deficient CD4 T cells. The TCR-induced ERK1/2, JNK, and p38 MAPKs activation was also defective in Mekk3-deficient CD4 T cells. In vitro, MEKK3 is not required for Th1 and Th2 cell differentiation. Notably, under a nonpolarizing condition (Th0), Mekk3 deficiency led to a significant reduction of IFN-γ production in CD4 T cells. Furthermore, the IL-12/IL-18–driven IFN-γ production and MAPK activation in Mekk3-deficient T cells was not affected suggesting that MEKK3 may selectively mediate the TCR-induced MAPK signals for IFN-γ production. Finally, we found that MEKK3 activation by TCR stimulation requires Rac1/2. Taken together, our study reveals a specific role of MEKK3 in mediating the TCR signals for IFN-γ production.

Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice

“…MEKK3 has been 29 A study also showed that MEKK3 regulates T-cell receptor-mediated ERK1/2, p38, and JNK MAPK activation in CD4 T cells. 15 In our study, we found that MEKK3 is responsible for activation of ERK1/2 and JNK2, but not p38, ERK5, or JNK1, in platelets. Adam et al claimed that JNK1 plays important roles in platelet activation and proposed that JNK2 also contributes to platelet aggregation, based on the observation of further inhibitory effects of the JNK inhibitor SP600125 on the aggregation of JNK1-deficient platelets.…”

“…[26][27][28] MEKK3 was reported to activate MAPKs. [14][15][16][17]29 The activation of p38, ERK1/2, JNK1/2, and ERK5 in MEKK3 f/f and MEKK3 2/2 platelets was determined. MEKK3 deficiency did not affect the activation of p38, JNK1, or ERK5, but it greatly impaired the activation of ERK1/2 and JNK2 induced by thrombin, ADP, U46619, or collagen (Figure 4C-D; supplemental Figure 4A-C).…”

“…13 MEKK3, a member of the MAP3K family, is an important activator of MAPK pathways. 14,15 Although MEKK3 plays essential roles in cardiovascular development 16 and immune responses, 17 its functions in platelet activation and thrombosis remain unknown. Here, using megakaryocyte/platelet-specific MEKK3-deletion (MEKK3 2/2 ) mice, we unravel an undocumented role for MEKK3 in platelet activation, thrombosis, and myocardial infarct expansion.…”

Mechanisms of Rapid Induction of Interleukin-22 in Activated T Cells and Its Modulation by Cyclosporin A

“…Although molecular details of IKK␣ activation are still cloudy it is noteworthy that MEKK3 is supposed to be located upstream of IKKs (54). A recent report in fact documents the pivotal role of MEKK3 for TCR-driven T cell activation and subsequent engagement of ERK1/2 as well as cytokine production (55). The remarkable potency of the MEK1/2 inhibitor U0126 detected herein to inhibit IL-22 expression is certainly of note in this context.…”

Transcription Factors NRF2 and NF-κB Are Coordinated Effectors of the Rho Family, GTP-binding Protein RAC1 during Inflammation

“…It seems that NRF2 induction through RAC1 is KEAP1-independent in our model even though KEAP1 overexpression inhibits RAC1 on the formation of E-cadherin-mediated cell-cell adhesion (37). It has been widely reported that RAC1 participates in several signaling kinase pathways, including MAPKs and PI3K (38,39). Our group has reported a KEAP-independent regulation of NRF2 that relies on signaling kinases PI3K/AKT (40).…”