NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages
This study investigates the role of NIK in activating specific inflammatory genes in macrophages, focusing on the effect of a mutation in NIK found in alymphoplasia (<i>aly</i>/<i>aly</i>) mice. Mouse peritoneal macrophages from <i>aly</i>/<i>aly</i> m...
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2025-01-01
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| author | Natalia Cuesta Anna D. Staniszewska Cristóbal Moreno Carmen Punzón Manuel Fresno |
| author_facet | Natalia Cuesta Anna D. Staniszewska Cristóbal Moreno Carmen Punzón Manuel Fresno |
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| description | This study investigates the role of NIK in activating specific inflammatory genes in macrophages, focusing on the effect of a mutation in NIK found in alymphoplasia (<i>aly</i>/<i>aly</i>) mice. Mouse peritoneal macrophages from <i>aly</i>/<i>aly</i> mice showed a severe defect in the production of some pro-inflammatory cytokines, such as IL-12. This effect seemed to take place at the transcriptional level, as shown by the reduced transcription of <i>Il12b</i> and <i>Il12a</i> in <i>aly</i>/<i>aly</i> macrophages after exposure to the TLR4 agonist LPS. Immunoprecipitation studies showed that the binding of NIK to c-Rel was not efficient in RAW 264.7 cells over-expressing the <i>aly</i>/<i>aly</i> mutation. In addition, the shuttling of c-Rel to the nucleus was shown to be impaired in <i>aly</i>/<i>aly</i> macrophages in response to LPS. When looking more specifically at the regulation of the <i>Il12b</i> promoter, we found that c-Rel bound to the NF-kB consensus sequence in macrophages from WT mice 1 hr. after LPS challenge, whereas in <i>aly</i>/<i>aly</i> macrophages, the transcription factor bound to the promoter was p65. These findings indicate that NIK is essential for efficient c-Rel activation and proper inflammatory responses. NIK dysfunction could lead to weakened immune responses, and targeting this pathway may help in developing therapies for immune-related conditions. |
| format | Article |
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| institution | Kabale University |
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| spelling | doaj-art-f6f23fd397814878a555a6556bf37fbb2025-01-24T13:23:22ZengMDPI AGBiology2079-77372025-01-011413310.3390/biology14010033NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in MacrophagesNatalia Cuesta0Anna D. Staniszewska1Cristóbal Moreno2Carmen Punzón3Manuel Fresno4Department of Cell Biology and Histology, School of Medicine, Universidad Complutense de Madrid, Avda Complutense s/n, 28040 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid—Consejo Superior de Investigaciones Científicas, Nicolás Cabrera 1, 28049 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid—Consejo Superior de Investigaciones Científicas, Nicolás Cabrera 1, 28049 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid—Consejo Superior de Investigaciones Científicas, Nicolás Cabrera 1, 28049 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid—Consejo Superior de Investigaciones Científicas, Nicolás Cabrera 1, 28049 Madrid, SpainThis study investigates the role of NIK in activating specific inflammatory genes in macrophages, focusing on the effect of a mutation in NIK found in alymphoplasia (<i>aly</i>/<i>aly</i>) mice. Mouse peritoneal macrophages from <i>aly</i>/<i>aly</i> mice showed a severe defect in the production of some pro-inflammatory cytokines, such as IL-12. This effect seemed to take place at the transcriptional level, as shown by the reduced transcription of <i>Il12b</i> and <i>Il12a</i> in <i>aly</i>/<i>aly</i> macrophages after exposure to the TLR4 agonist LPS. Immunoprecipitation studies showed that the binding of NIK to c-Rel was not efficient in RAW 264.7 cells over-expressing the <i>aly</i>/<i>aly</i> mutation. In addition, the shuttling of c-Rel to the nucleus was shown to be impaired in <i>aly</i>/<i>aly</i> macrophages in response to LPS. When looking more specifically at the regulation of the <i>Il12b</i> promoter, we found that c-Rel bound to the NF-kB consensus sequence in macrophages from WT mice 1 hr. after LPS challenge, whereas in <i>aly</i>/<i>aly</i> macrophages, the transcription factor bound to the promoter was p65. These findings indicate that NIK is essential for efficient c-Rel activation and proper inflammatory responses. NIK dysfunction could lead to weakened immune responses, and targeting this pathway may help in developing therapies for immune-related conditions.https://www.mdpi.com/2079-7737/14/1/33macrophagesNIKIL-12c-Rel |
| spellingShingle | Natalia Cuesta Anna D. Staniszewska Cristóbal Moreno Carmen Punzón Manuel Fresno NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages Biology macrophages NIK IL-12 c-Rel |
| title | NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages |
| title_full | NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages |
| title_fullStr | NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages |
| title_full_unstemmed | NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages |
| title_short | NF-κB-Inducing Kinase Is Essential for Effective c-Rel Transactivation and Binding to the <i>Il12b</i> Promoter in Macrophages |
| title_sort | nf κb inducing kinase is essential for effective c rel transactivation and binding to the i il12b i promoter in macrophages |
| topic | macrophages NIK IL-12 c-Rel |
| url | https://www.mdpi.com/2079-7737/14/1/33 |
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