title: JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis.
abstract: OBJECTIVE
  To elucidate the nonredundant roles of JNK-1 and JNK-2 in antigen-induced arthritis (AIA).
  
  
  METHODS
  Mice that were genetically disrupted in Jnk1 or Jnk2 were primed by injection of methylated bovine serum albumin (mBSA) in Freund's complete adjuvant and then challenged on day 21 by intraarticular injection of mBSA into the right knee. Bone marrow chimeras were generated and similarly treated. Joints were harvested and prepared for histologic assessment. T cell responses were verified by cytokine and proliferation responses, and relative immunoglobulin responses were measured by enzyme-linked immunosorbent assay. Cytokine messenger RNA expression levels were measured by quantitative polymerase chain reaction analysis. Thioglycollate-elicited and zymosan A-elicited macrophage recruitment was tested in vivo, and cell migration was tested in vitro. The peptide inhibitor D-JNKi was injected daily starting 4 days after intraarticular injection of mBSA into wild-type (WT) mice, and inflammation was scored histologically.
  
  
  RESULTS
  JNK-1-deficient, but not JNK-2-deficient, mice had a reduction in inflammatory cell infiltration and joint damage. This effect was primarily restricted to hematopoietic cells, but B and T cell responses were preserved in mBSA-injected mice. JNK-1-deficient macrophages produced cytokines and chemokines at a level comparable to that in their WT counterparts. However, macrophage migration was impaired in vivo and in vitro. Targeting JNK with the peptide inhibitor D-JNKi dramatically reduced inflammation and joint destruction in WT mice.
  
  
  CONCLUSIONS
  AIA is dependent on JNK-1, but not JNK-2. JNK-1 is a promising molecular target for reducing autoimmune inflammation, since its inhibition impairs macrophage migration.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093-0663, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ronacher
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000235:genetics* / Q000473:pathology; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D002678:Chimera / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000276:immunology; D007136:Immunoglobulins / Q000276:immunology; D007719:Knee Joint / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013864:Thioglycolates / Q000276:immunology; D015054:Zymosan / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007136:Immunoglobulins; D010455:Peptides; D013864:Thioglycolates; C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D005620:Freund's Adjuvant; D015054:Zymosan; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; C478085:D-JNKI-1