Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice

Abstract

Mitogen kinase kinase 4 (MKK4) and mitogen kinase kinase 7 (MKK7) are members of the MAP2K family that can activate downstream mitogen-activated protein kinases (MAPKs). MKK4 has been implicated in the activation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, while MKK7 has been reported to activate only JNK in response to different stimuli. The stimuli, as well as the cell type determine which MAP2K member will mediate a given response. In various cell types, MKK7 contributes to the activation of downstream MAPKs, JNK, which is known to regulate essential cellular processes, such as cell death, differentiation, stress response, and cytokine secretion. Previous studies have also implicated the role of MKK7 in stress signaling pathways and cytokine production. However, little is known about the degree to which MKK4 and MKK7 contribute to innate immune responses in macrophages or during inflammation in vivo. To address this question and to elucidate the role of MKK4 and MKK7 in macrophage and in vivo, we developed MKK4- and MKK7-deficient mouse models with tamoxifen-inducible Rosa26 CreERT. This study reports that MKK7 is required for JNK activation both in vitro and in vivo. Additionally, we demonstrated that MKK7 in macrophages is necessary for lipopolysaccharide (LPS)-induced cytokine production, M1 polarization, and migration, which appear to be a major contributor to the inflammatory response in vivo. Conversely, MKK4 plays a significant, but minor role in cytokine production in vivo.

Mitogen-activated protein kinase kinase 7 in inflammatory, cancer, and neurological diseases

“…Similar to the migration and invasion data, MKK7 is essential for macrophage polarization to M1 inflammatory macrophage and, therefore, for inflammatory cytokine production (Caliz et al, 2021). The ability of MKK7 to control polarization and migration of macrophages suggests that MKK7 contributes to the regulation of inflammatory responses (Caliz et al, 2021). Data from this study illustrate the MKK7 pathway as a plausible target for therapeutic drug development beneficial for the treatment of sepsis and inflammation.…”

“…Notably, significant blockage formed in the migration and invasion of macrophages in MKK7-deficient mice compared to the control. Similar to the migration and invasion data, MKK7 is essential for macrophage polarization to M1 inflammatory macrophage and, therefore, for inflammatory cytokine production (Caliz et al, 2021). The ability of MKK7 to control polarization and migration of macrophages suggests that MKK7 contributes to the regulation of inflammatory responses (Caliz et al, 2021).…”

“…Studies have also displayed the JNK-independent role of MKK4 ( Hickson et al, 2006 ; Caliz et al, 2021 ). Previously, MKK4 has been shown to interact with p38 MAPKs ( Brancho et al, 2003 ; Wang et al, 2007 ).…”

“…Previously, MKK4 has been shown to interact with p38 MAPKs ( Brancho et al, 2003 ; Wang et al, 2007 ). However, a recent study has shown that MKK7 can also affect p38 signaling in vivo ( Caliz et al, 2021 ). This non-canonical role of MKK7 has not been adequately explored.…”

“…The central dogma defines MKK4/7 as major activators of the JNK pathway ( Figure 1 ) and MKK3/6 as responsible for the activation of p38 MAPKs ( Davis 2000 ; Cargnello and Roux 2011 ). However, recent studies have clearly demonstrated that there are overlaps of MKKs functions in the regulation of JNK and p38 MAPK in vivo ( Caliz et al, 2021 ) . In vitro , JNKs are activated via the sequential phosphorylation of upstream protein kinases that comprises two dual-specificity MAP kinase kinases (MKK4 and MKK7) [4].…”