Deficiency in p38β MAPK Fails to Inhibit Cytokine Production or Protect Neurons against Inflammatory Insult in In Vitro and In Vivo Mouse Models

Abstract

The p38 MAPK pathway plays a key role in regulating the production of proinflammatory cytokines, such as TNFα and IL-1β, in peripheral inflammatory disorders. There are four major isoforms of p38 MAPK (p38α, β, δ, γ), with p38α and p38β the targets of most p38 MAPK inhibitor drugs. Our previous studies demonstrated that the p38α MAPK isoform is an important contributor to stressor-induced proinflammatory cytokine up-regulation and neurotoxicity in the brain. However, the potential role of the p38β 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 p38β 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 p38β KO mice after administration of LPS by intraperitoneal or intracerebroventricular injection. WT and p38β KO microglia/neuron co-cultures showed similar levels of TNFα and IL-1β production in response to LPS treatment, and no differences in LPS-induced neurotoxicity. The in vitro results were confirmed in vivo, where levels of TNFα and IL-1β in the CNS were not significantly different between WT or p38β KO mice after LPS insult. Our results suggest that, similar to peripheral inflammation, p38α is critical but p38β MAPK is dispensable in the brain in regards to proinflammatory cytokine production and neurotoxicity induced by LPS inflammatory insult.

p38 MAP kinases in the heart

“…Considering the severity of phenotypes in isoform specific knockout mice, p38α MAPK seems to be the major isofom of the family at least during development and inflammatory responses, although p38β MAPK, p38γ MAPK, and p38δ MAPK have also pivotal roles under other conditions. (Aouadi, Binetruy, Caron, Le Marchand-Brustel, & Bost, 2006; Xing, Bachstetter, & Van Eldik, 2013). …”

Phospholipase A2 of Peroxiredoxin 6 Plays a Critical Role in Cerebral Ischemia/Reperfusion Inflammatory Injury

“…In this system, the two kinds of cells share the same medium and interact through diffusible molecules only. As reported by others, we adopted the Neurobasal medium to meet higher nutrition requirements for neurons (Xing et al, 2013). Before OGD/R treatment, microglia and neurons were co-cultured 24 h for utmost microglial activation.…”

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

“…73 Using cells within the CNS, several studies have demonstrated that the p38 MAPKa isoform is a relatively more important contributor to stressor-induced proinflammatory cytokine production and neurotoxicity compared with the p38b isoform. [74][75][76] Several studies have reported that SB203580, a typical inhibitor of p38 MAPKa and p38 MAPKb, rescues RGCs from NMDA and optic nerve injury, suggesting the involvement of p38 MAPKa and p38 MAPKb in RGC survival. 77,78 However, the roles of the other p38 isoforms in neuronal cells have yet to be elucidated.…”