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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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
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| Series: | Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-7737/14/1/33 |
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| Summary: | 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. |
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| ISSN: | 2079-7737 |