Inflammation in the central nervous system (CNS) is a common feature of 
age-related neurodegenerative diseases. Proinflammatory cytokines, such as IL-1β 
and TNFα, are produced primarily by cells of the innate immune system, namely 
microglia in the CNS, and are believed to contribute to the neuronal damage seen 
in the disease. The p38 mitogen-activated protein kinase (MAPK) is one of the 
kinase pathways that regulate the production of IL-1β and TNFα. Importantly, 
small molecule inhibitors of the p38 MAPK family have been developed and show 
efficacy in blocking the production of IL-1β and TNFα. The p38 family consists 
of at least four isoforms (p38α, β, γ, δ) encoded by separate genes. Recent 
studies have begun to demonstrate unique functions of the different isoforms, 
with p38α being implicated as the key isoform involved in CNS inflammation. 
Interestingly, there is also emerging evidence that two downstream substrates of 
p38 may have opposing roles, with MK2 being pro-inflammatory and MSK1/2 being 
antiinflammatory. This review discusses the properties, function and regulation 
of the p38 MAPK family as it relates to cytokine production in the CNS.