A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activationReportar como inadecuado




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Arthritis Research and Therapy

, 14:R9

First Online: 17 January 2012Received: 14 June 2011Revised: 13 December 2011Accepted: 17 January 2012

Abstract

IntroductionCelecoxib, 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 Ca-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.

MethodsTo 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 macophages, and neutrophil recruitment were also evaluated.

ResultsTFM-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.

ConclusionThese results indicate that TFM-C may serve as an effective new disease-modifying drug for treatment of arthritis, such as rheumatoid arthritis.

AbbreviationsB6C57BL-6J

CIIanti-type II collagen

CAIAtype II collagen antibody-induced arthritis

CFAcomplete Freund-s adjuvant

CIAcollagen-induced arthritis

COX-2cycolooxygenase-2

EAEexperimental autoimmune encephalomyelitis

ELISAenzyme-linked immunosorbent assay

IFAincomplete Freund-s adjuvant

ILinterleukin

LPSlipopolysaccharide

MOGmyelin oligodendrocyte glycoprotein

MtbMycobacterium tuberculosis

PBSphosphate-buffered saline

TFM-Ca trifluoromethyl analogue of celecoxib

TNFtumor necrosis factor.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3683 contains supplementary material, which is available to authorized users.

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