title: The p38alpha mitogen-activated protein kinase limits the CNS proinflammatory cytokine response to systemic lipopolysaccharide, potentially through an IL-10 dependent mechanism.
abstract: BACKGROUND
  The p38α mitogen-activated protein kinase (MAPK) is a well-characterized intracellular kinase involved in the overproduction of proinflammatory cytokines from glia. As such, p38α appears to be a promising therapeutic target for neurodegenerative diseases associated with neuroinflammation. However, the in vivo role of p38α in cytokine production in the CNS is poorly defined, and prior work suggests that p38α may be affecting a yet to be identified negative feedback mechanism that limits the acute, injury-induced proinflammatory cytokine surge in the CNS.
  
  
  METHODS
  To attempt to define this negative feedback mechanism, we used two in vitro and two in vivo models of neuroinflammation in a mouse where p38α is deficient in cells of the myeloid lineage.
  
  
  RESULTS
  We found that p38α in myeloid cells has an important role in limiting amplitude of the acute proinflammatory cytokine response to a systemic inflammatory challenge. Moreover, we identified IL-10 as a potential negative feedback mechanism regulated by p38α.
  
  
  CONCLUSIONS
  Our data suggest that p38α regulates a proper balance between the pro- and anti-inflammatory cytokine responses to systemic inflammation, and that if circulating IL-10 levels are not elevated to counter-balance the increased systemic proinflammatory responses, the spread of the inflammatory response from the periphery to the CNS is exaggerated.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.forename: Bin
authors.initials: B
authors.lastname: Xing
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, 800 S, Limestone Street, Lexington 40536, KY, USA. linda.vaneldik@uky.edu.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism*; D004333:Drug Administration Routes; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics; D009154:Mutation / Q000235:genetics
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14