Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice
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 act...
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MDPI AG
2021-08-01
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| Series: | International Journal of Molecular Sciences |
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| author | Amada D. Caliz Hyung-Jin Yoo Anastassiia Vertii Ana C. Dolan Cathy Tournier Roger J. Davis John F. Keaney Shashi Kant |
| author_facet | Amada D. Caliz Hyung-Jin Yoo Anastassiia Vertii Ana C. Dolan Cathy Tournier Roger J. Davis John F. Keaney Shashi Kant |
| author_sort | Amada D. Caliz |
| collection | DOAJ |
| description | 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<sup>ERT</sup>. 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. |
| first_indexed | 2024-03-10T08:10:45Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T08:10:45Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6284482b7177410c8fbdff7e2bacb3842023-11-22T10:42:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-012217936410.3390/ijms22179364Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in MiceAmada D. Caliz0Hyung-Jin Yoo1Anastassiia Vertii2Ana C. Dolan3Cathy Tournier4Roger J. Davis5John F. Keaney6Shashi Kant7Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01655, USADivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UKProgram in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USADivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USADivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USAMitogen 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<sup>ERT</sup>. 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.https://www.mdpi.com/1422-0067/22/17/9364kinaseMAPKcytokinesignalinginflammation |
| spellingShingle | Amada D. Caliz Hyung-Jin Yoo Anastassiia Vertii Ana C. Dolan Cathy Tournier Roger J. Davis John F. Keaney Shashi Kant Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice International Journal of Molecular Sciences kinase MAPK cytokine signaling inflammation |
| title | Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice |
| title_full | Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice |
| title_fullStr | Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice |
| title_full_unstemmed | Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice |
| title_short | Mitogen Kinase Kinase (MKK7) Controls Cytokine Production In Vitro and In Vivo in Mice |
| title_sort | mitogen kinase kinase mkk7 controls cytokine production in vitro and in vivo in mice |
| topic | kinase MAPK cytokine signaling inflammation |
| url | https://www.mdpi.com/1422-0067/22/17/9364 |
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