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The c-Jun N-terminal kinases in cerebral microglia: immunological functions in the brain

Item Type:Article
Title:The c-Jun N-terminal kinases in cerebral microglia: immunological functions in the brain
Creators Name:Hidding, U. and Mielke, K. and Waetzig, V. and Brecht, S. and Hanisch, U. and Behrens, A. and Wagner, E. and Herdegen, T.
Abstract:The c-Jun N-terminal kinases (JNKs) exert a pleiotrophy of physiological and pathological actions. This is also true for the immune system. Disruption of the JNK locus results in substantial functional deficits of peripheral T-cells. In contrast to circulating immune cells and the role of p38, the presence and function of JNKs in the immune cells of the brain remain to be defined. Here, we report on the expression and activation of JNKs in cultivated microglia from neonatal rats and from mice with targeted disruption of the JNK locus and the N-terminal mutation of c-Jun (c-JunAA), respectively. JNK1, 2 and 3 mRNA and proteins were all expressed in microglia. Following stimulation with LPS (100ng/mL), a classical activator of microglia, JNKs were rapidly activated and this activation returns to basal levels within 4hr. Following LPS and other stimuli such as thrombin (10-50unit/mL), the activation of JNKs went along with the N-terminal phosphorylation of c-Jun which persisted for at least 8hr. Indirect inhibition of JNK by CEP-11004 (0.5-2{mu}M), an inhibitor of mixed-lineage kinases (MLK), reduced the LPS-induced phosphorylation of both, JNK and c-Jun, by around 50%, and attentuated the LPS-induced the alterations in microglial morphology. Finally, JNKs are involved in the control of cytokine release since both, incubation with CEP-11004 and disruption of the JNK1 locus enhanced the release of TNF{alpha}, IL-6 and IL-12. Our findings provide insight in so far unknown functions of JNKs in cerebral immune cells. These observations are also important for the wide spread efforts to develop JNK-inhibitors as neuroprotective drugs which, however, might trigger pro-inflammatory processes.
Keywords:C-Jun, C-Jun N-Terminal Kinases, Immune Cells, Microglia, Mixed-Lineage Kinases, Neurodegeneration, Animals, Mice
Source:Biochemical Pharmacology
Page Range:781-788
Date:September 2002
Official Publication:https://doi.org/10.1016/S0006-2952(02)01139-5
PubMed:View item in PubMed

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