UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; Program in Molecular Medicine; Davis Lab

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Document Type



Amino Acids, Peptides, and Proteins | Cell Biology | Enzymes and Coenzymes | Immunology and Infectious Disease | Molecular Biology


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 Cre(ERT). 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.


MAPK, cytokine, inflammation, kinase, signaling

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Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (

DOI of Published Version



Caliz AD, Yoo HJ, Vertii A, Dolan AC, Tournier C, Davis RJ, Keaney JF Jr, Kant S. Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice. Int J Mol Sci. 2021 Aug 29;22(17):9364. doi: 10.3390/ijms22179364. PMID: 34502275; PMCID: PMC8431745. Link to article on publisher's site

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International journal of molecular sciences

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.