The role of p38 mitogen-activated protein kinase in IL-1 beta transcription

Citation
Jj. Baldassare et al., The role of p38 mitogen-activated protein kinase in IL-1 beta transcription, J IMMUNOL, 162(9), 1999, pp. 5367-5373
Citations number
53
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
0022-1767 → ACNP
Volume
162
Issue
9
Year of publication
1999
Pages
5367 - 5373
Database
ISI
SICI code
0022-1767(19990501)162:9<5367:TROPMP>2.0.ZU;2-Q
Abstract
Several reports have shown that bicyclic imidazoles, specific inhibitors of the p38 mitogen-activated protein kinase (MAPK), block cytokine synthesis at the translational level. In this study, we examined the role of p38 MAPK in the regulation of the IL-1 beta cytokine gene in monocytic cell lines u sing the bicyclic imidazole SB203580. Addition of SB203580 30 min before st imulation of monocytes with LPS inhibited IL-1 beta protein and steady stat e message in a dose-dependent manner in both RAW263.7 and J774 cell lines. The loss of IL-1 beta message was due mainly to inhibition of transcription , since nuclear run-off analysis showed an similar to 80% decrease in speci fic IL-1 RNA synthesis. In contrast, SB203580 had no effect on the synthesi s of TNF-alpha message. LPS-stimulated p38 MAPK activity in the RAW264.7 ce lls was blocked by SB203580, as measured by the inhibition of MAPKAP2 kinas e activity a downstream target of the p38 MAPK. CCAATT/enhancer binding pro tein (C/EBP)/NFIL-6-driven chloramphenicol acetyl: transferase (CAT) report er activity was sensitive to SB203580, indicating that C/EBP/NFIL-6 transcr iption factor(s) are also targets of p38 MAPK. In contrast, transfected CAT constructs containing NF-kappa B elements were only partially inhibited (s imilar to 35%) at the highest concentration of SB203580 after LPS stimulati on. As measured by ERISA, LPS-stimulated NF-kappa B activation was not affe cted by SB203580. Overall, the results demonstrate, for the first time, a r ole for p38 MAPK in IL-1 beta transcription by acting through C/EBP/NFIL-6 transcription factors.