title: A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activation.
abstract: BACKGROUND
  Celecoxib, a highly specific cyclooxygenase-2 (COX-2) inhibitor has been reported to have COX-2-independent immunomodulatory effects. However, celecoxib itself has only mild suppressive effects on arthritis. Recently, we reported that a 4-trifluoromethyl analogue of celecoxib (TFM-C) with 205-fold lower COX-2-inhibitory activity inhibits secretion of IL-12 family cytokines through a COX-2-independent mechanism that involves Ca2+-mediated intracellular retention of the IL-12 polypeptide chains. In this study, we explored the capacity of TFM-C as a new therapeutic agent for arthritis.
  
  
  METHODS
  To induce collagen-induced arthritis (CIA), DBA1/J mice were immunized with bovine type II collagen (CII) in Freund's adjuvant. Collagen antibody-induced arthritis (CAIA) was induced in C57BL/6 mice by injecting anti-CII antibodies. Mice received 10 μg/g of TFM-C or celecoxib every other day. The effects of TFM-C on clinical and histopathological severities were assessed. The serum levels of CII-specific antibodies were measured by ELISA. The effects of TFM-C on mast cell activation, cytokine producing capacity by macrophages, and neutrophil recruitment were also evaluated.
  
  
  RESULTS
  TFM-C inhibited the severity of CIA and CAIA more strongly than celecoxib. TFM-C treatments had little effect on CII-specific antibody levels in serum. TFM-C suppressed the activation of mast cells in arthritic joints. TFM-C also suppressed the production of inflammatory cytokines by macrophages and leukocyte influx in thioglycollate-induced peritonitis.
  
  
  CONCLUSIONS
  These results indicate that TFM-C may serve as an effective new disease-modifying drug for treatment of arthritis, such as rheumatoid arthritis.
authors.affiliation: Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Chiba
authors.forename: Miho
authors.initials: M
authors.lastname: Mizuno
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tomi
authors.forename: Ryohsuke
authors.initials: R
authors.lastname: Tajima
authors.forename: Iraide
authors.initials: I
authors.lastname: Alloza
authors.forename: Alessandra
authors.initials: A
authors.lastname: di Penta
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D000068579:Celecoxib; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013864:Thioglycolates; D020298:U937 Cells
chemical_list: D018501:Antirheumatic Agents; D024043:Collagen Type II; D016207:Cytokines; D011720:Pyrazoles; D013449:Sulfonamides; D013864:Thioglycolates; D000068579:Celecoxib