title: Interleukin-1 and tumor necrosis factor α blockade treatment of experimental polymyositis in mice.
abstract: OBJECTIVE
  Histologic studies of the muscles suggest that cytokines are involved in inflammatory myopathy. The therapeutic effects of cytokine blockade are controversial, with anecdotal reports of clinical efficacy. The aim of this study was to discern the significance of interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) as therapeutic targets in polymyositis (PM) by studying their involvement and the effects of their blockade in C protein-induced myositis (CIM), a murine model of PM.
  
  
  METHODS
  C57BL/6 mice were immunized with recombinant skeletal C protein fragments to induce CIM. The expression of IL-1 and TNFα in the muscles of mice with CIM was detected using immunohistochemical and real-time polymerase chain reaction analyses. After the onset of myositis, the mice with CIM were treated with recombinant IL-1 receptor antagonist (IL-1Ra), anti-IL-1R monoclonal antibody, recombinant TNF receptor (p75)-fusion protein (TNFR-Fc), or anti-TNFα monoclonal antibody. The muscles were examined histologically for the severity of myositis.
  
  
  RESULTS
  IL-1α- and TNFα-positive macrophages were observed in the muscle tissue of mice with CIM as early as 7 days after immunization. IL-1α, IL-1β, and TNFα expression in the muscles increased as the severity of myositis peaked, at both the messenger RNA and protein levels. Continuous subcutaneous delivery of IL-1Ra resulted in suppression of established CIM. Intermittent delivery (1-day intervals) of anti-IL-1R monoclonal antibody suppressed myositis, while intermittent delivery of IL-1Ra did not suppress myositis. Treatment with anti-TNFα monoclonal antibody and with TNFR-Fc also reduced the severity of CIM.
  
  
  CONCLUSIONS
  IL-1 and TNF blockade ameliorated CIM after disease onset and should potentially be a new strategy for the treatment of inflammatory myopathy. As IL-1 blockade, treatment with anti-IL-1R monoclonal antibody appeared more feasible than the other approaches.
authors.affiliation: Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sugihara
authors.forename: Naoko
authors.initials: N
authors.lastname: Okiyama
authors.forename: Naoto
authors.initials: N
authors.lastname: Watanabe
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyasaka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohsaka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017285:Polymyositis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept