The p38 MAP Kinase Family as Regulators of Proinflammatory Cytokine Production in Degenerative Diseases of the CNS

Abstract

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.

Keywords: Microglia; Neurodegeneration; Neuroinflammation; Protein kinase; Signal Transduction.

Figure 1:

Overview of the p38 MAPK signal transduction pathway involved in cytokine production. Extracelluar stimuli activate receptor and receptor associated proteins, which then transduce the activating signal into cellular responses by a three step MAPK pathway (MAPKKK, MAPKK, MAPK) that leads to p38 activation. Activated p38 can directly activate transcription factors or can act indirectly via two downstream kinases MK2 and MSK1/2. The cellular response produced can have many paracrine functions but can also have autocrine functions leading to further activation or suppression of the p38 pathway.

Figure 2:

Feedback mechanisms regulating p38α. Inflammatory signals, such as TNFα and IL-1β, can activate the p38 pathway. Two downstream kinases of p38 are MK2 and MSK1/2. MK2 can promote an increase in TNFα, IL-1β and IL-6. These pro-inflammatory cytokines can then feed back onto the cell, activating the same pathway and amplifying the inflammation. MSK1/2 produces the phosphatase DUSP1, which dephosphorylates and deactivates p38. Two antiinflammatory cytokines IL-1ra and IL-10 are also regulated by MSK1/2 activation. These cytokines have the potential to antagonize the effects of IL-1β and suppress the inflammatory response.