Deficiency in p38b MAPK Fails to Inhibit Cytokine Production or Protect Neurons against Inflammatory Insult in In Vitro and In Vivo Mouse Models

The p38 MAPK pathway plays a key role in regulating the production of proinflammatory cytokines, such as TNFa and IL-1b, in peripheral inflammatory disorders. There are four major isoforms of p38 MAPK (p38a, b, d, c), with p38a and p38b the targets of most p38 MAPK inhibitor drugs. Our previous studies demonstrated that the p38a MAPK isoform is an important contributor to stressor-induced proinflammatory cytokine up-regulation and neurotoxicity in the brain. However, the potential role of the p38b MAPK isoform in CNS proinflammatory cytokine overproduction and neurotoxicity is poorly understood. In the current studies, we used primary microglia from wild type (WT) and p38b knockout (KO) mice in co-culture with WT neurons, and measured proinflammatory cytokines and neuron death after LPS insult. We also measured neuroinflammatory responses in vivo in WT and p38b KO mice after administration of LPS by intraperitoneal or intracerebroventricular injection. WT and p38b KO microglia/neuron co-cultures showed similar levels of TNFa and IL-1b production in response to LPS treatment, and no differences in LPS-induced neurotoxicity. The in vitro results were confirmed in vivo, where levels of TNFa and IL-1b in the CNS were not significantly different between WT or p38b KO mice after LPS insult. Our results suggest that, similar to peripheral inflammation, p38a is critical but p38b MAPK is dispensable i