title: Decreased collagen-induced arthritis severity and adaptive immunity in MKK-6-deficient mice.
abstract: OBJECTIVE
  The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK-3 and MKK-6 deficiency in the collagen-induced arthritis (CIA) model.
  
  
  METHODS
  Wild-type (WT), MKK-3(-/-) , and MKK-6(-/-)  mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro-computed tomography. Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction.
  
  
  RESULTS
  MKK-6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK-3 had an intermediate effect. Joint damage was minimal in arthritic MKK-6(-/-)  mice and intermediate in MKK-3(-/-)  mice compared with WT mice. MKK-6(-/-)  mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK-3(-/-)  mice. In vitro T cell assays showed reduced proliferation and interleukin-17 (IL-17) production by lymph node cells from MKK-6(-/-)  mice in response to type II collagen. Gene expression of synovial IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice.
  
  
  CONCLUSIONS
  Reduced disease severity in MKK-6(-/-)  mice correlated with decreased anticollagen antibody responses, indicating that MKK-6 is a crucial regulator of inflammatory joint destruction in CIA. MKK-6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA.
authors.affiliation: University of California San Diego at La Jolla, CA 92093, USA. dhammaker@ucsd.edu
authors.forename: Deepa
authors.initials: D
authors.lastname: Hammaker
authors.forename: Katharyn
authors.initials: K
authors.lastname: Topolewski
authors.forename: Meghan
authors.initials: M
authors.lastname: Edgar
authors.forename: Toshio
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Akihisa
authors.initials: A
authors.lastname: Fukushima
authors.forename: David L
authors.initials: DL
authors.lastname: Boyle
authors.forename: Esther Cory
authors.initials: EC
authors.lastname: Burak
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sah
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D002417:Cattle; D003094:Collagen / Q000276:immunology / Q000494:pharmacology; D005260:Female; D007178:Inbreeding; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007596:Joints / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D015850:Interleukin-6; D003094:Collagen; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3