title: Macrophage migration inhibitory factor regulates neutrophil chemotactic responses in inflammatory arthritis in mice.
abstract: OBJECTIVE
  Macrophage migration inhibitory factor (MIF) facilitates multiple aspects of inflammatory arthritis, the pathogenesis of which has been significantly linked to the activity of neutrophils. The effects of MIF on neutrophil recruitment are unknown. This study was undertaken to investigate the contribution of MIF to the regulation of neutrophil chemotactic responses.
  
  
  METHODS
  K/BxN serum-transfer arthritis was induced in wild-type (WT), MIF(-/-) , and monocyte chemotactic protein 1 (MCP-1; CCL2)-deficient mice as well as in WT mice treated with monoclonal antibodies to cytokine-induced neutrophil chemoattractant (anti-KC). Leukocyte trafficking in vivo was examined using intravital microscopy, and neutrophil function in vitro was examined using migration chambers and assessment of MAP kinase activation.
  
  
  RESULTS
  K/BxN serum-transfer arthritis was markedly attenuated in MIF(-/-) mice, with reductions in the clinical and histologic severity of arthritis and the synovial expression of KC and interleukin-1. Arthritis was also reduced by anti-KC antibody treatment, but not in MCP-1-deficient mice. In vivo, neutrophil recruitment responses to KC were reduced in MIF(-/-) mice. Similarly, MIF(-/-) mouse neutrophils exhibited reduced chemotactic responses to KC in vitro, despite displaying unaltered chemokine receptor expression. Reduced chemotactic responses of MIF(-/-) mouse neutrophils were associated with reduced phosphorylation of p38 and ERK MAP kinases.
  
  
  CONCLUSIONS
  These findings suggest that MIF promotes neutrophil trafficking in inflammatory arthritis via facilitation of chemokine-induced migratory responses and MAP kinase activation. Therapeutic MIF inhibition could limit synovial neutrophil recruitment.
authors: Monash Medical Centre, Clayton, Victoria, Australia.
authors: Leilani L
authors: LL
authors: Santos
authors: Huapeng
authors: H
authors: Fan
authors: Pam
authors: P
authors: Hall
authors: Devi
authors: D
authors: Ngo
authors: Charles R
authors: CR
authors: Mackay
authors: Gunter
authors: G
authors: Fingerle-Rowson
authors: Richard
authors: R
authors: Bucala
authors: Michael J
authors: MJ
authors: Hickey
authors: Eric F
authors: EF
authors: Morand
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000503:physiopathology*; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D008263:Macrophage Migration-Inhibitory Factors; D048049:Extracellular Signal-Regulated MAP Kinases