title: IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy.
abstract: OBJECTIVE
  Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis.
  
  
  RESULTS
  Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s)IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor alpha (TNFalpha) and IL-1beta synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNFalpha antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNFalpha responded to IL-33 in chemotaxis.
  
  
  CONCLUSIONS
  These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFalpha therapy of inflammation.
authors.affiliation: Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil. waverri@uel.br
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Fabrício O
authors.initials: FO
authors.lastname: Souto
authors.forename: Silvio M
authors.initials: SM
authors.lastname: Vieira
authors.forename: Sergio C L
authors.initials: SC
authors.lastname: Almeida
authors.forename: Sandra Y
authors.initials: SY
authors.lastname: Fukada
authors.forename: Damo
authors.initials: D
authors.lastname: Xu
authors.forename: Jose C
authors.initials: JC
authors.lastname: Alves-Filho
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Ana T G
authors.initials: AT
authors.lastname: Guerrero
authors.forename: Rafaela B
authors.initials: RB
authors.lastname: Mattos-Guimaraes
authors.forename: Fabíola R
authors.initials: FR
authors.lastname: Oliveira
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Paulo
authors.initials: P
authors.lastname: Louzada-Junior
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002630:Chemotactic Factors / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin; D013583:Synovial Membrane / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D018501:Antirheumatic Agents; D002630:Chemotactic Factors; D016207:Cytokines; C506536:IL33 protein, human; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha