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

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 (100 ng/mL), a classical activator of microglia, JNKs were rapidly activated and this activation returns to basal levels within 4 hr. Following LPS and other stimuli such as thrombin (10-50 unit/mL), the activation of JNKs went along with the N-terminal phosphorylation of c-Jun which persisted for at least 8 hr. Indirect inhibition of JNK by CEP-11004 (0.5-2 muM), 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 TNFalpha, 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. (C) 2002 Elsevier Science Inc. All rights reserved.