title: Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6.
abstract: OBJECTIVE
  Inhibitors of p38 demonstrate limited benefit in rheumatoid arthritis (RA), perhaps due to the antiinflammatory functions of p38α. This study was performed to determine if selective deletion of p38α in macrophages affects the severity of arthritis and whether blocking upstream kinases in the p38 pathway, such as MKK-3 or MKK-6, avoids some of the limitations of p38 blockade.
  
  
  METHODS
  Wild-type (WT) mice and mice with selective deletion of p38α in macrophages (p38α(ΔLysM) ) were injected with K/BxN sera. Antigen-induced arthritis was also induced in p38α(ΔLysM)  mice. Mouse joint extracts were evaluated by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (qPCR), and Western blot analysis. Bone marrow-derived macrophages (BMMs) were stimulated with lipopolysaccharide (LPS) and were evaluated by qPCR and Western blotting. Bone marrow chimeras were generated using MKK-3(-/-)  and MKK-6(-/-)  mice, and K/BxN serum was administered to induce arthritis.
  
  
  RESULTS
  Compared to WT mice, p38α(ΔLysM)  mice had increased disease severity and delayed resolution of arthritis, which correlated with higher synovial inflammatory mediator expression and ERK phosphorylation. In contrast to WT BMMs cultured in the presence of a p38α/β inhibitor, LPS-stimulated MKK-6- and MKK-3-deficient BMMs had suppressed LPS-mediated interleukin-6 (IL-6) expression but had normal IL-10 production, dual-specificity phosphatase 1 expression, and MAPK phosphorylation. WT chimeric mice with MKK-6- and MKK-3-deficient bone marrow had markedly decreased passive K/BxN arthritis severity.
  
  
  CONCLUSIONS
  Inhibiting p38α in a disease that is dominated by macrophage cytokines, such as RA, could paradoxically suppress antiinflammatory functions and interfere with clinical efficacy. Targeting an upstream kinase that regulates p38 could be more effective by suppressing proinflammatory cytokines while preventing decreased IL-10 expression and increased MAPK activation.
authors.affiliation: University of California at San Diego, La Jolla CA 92093-0656, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.forename: Deepa
authors.initials: D
authors.lastname: Hammaker
authors.forename: Katharyn
authors.initials: K
authors.lastname: Topolewski
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007596:Joints / Q000378:metabolism; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D013154:Spleen / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482567:Map2k6 protein, mouse