A 4-trifluoromethyl analogue of celecoxib inhibits arthritis by suppressing innate immune cell activation

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 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.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.

Effect of red propolis on hamster cheek pouch angiogenesis in a new sponge implant model

“…This is in agreement with the literature, which shows celecoxib to have immunomodulating effects 30 .…”

Protection against Chikungunya virus induced arthralgia following prophylactic treatment with adenovirus vectored interferon (mDEF201)

“…The DBA/1J strain was selected based on the development of robust footpad swelling, availability and use in arthritis research (Chiba et al, 2012; Eros et al, 2009; Nishida et al, 2002). To characterize CHIKV replication and disease in this mouse strain, DBA/1J mice were inoculated with S27 CHIKV in the rear hind footpad and footpad swelling, virus titer of various tissues, cytokine levels, and weight change were quantified.…”

Urokinase plasminogen activator and receptor promote collagen-induced arthritis through expression in hematopoietic cells

“…Each of these cell types has been shown to express both uPA and uPAR, 19,[44][45][46][47] and each has been linked to arthritis pathogenesis in both RA and CIA. 20,33,[48][49][50][51] Whether uPA/uPAR-dependent mechanisms of arthritis pathogenesis occur through multiple hematopoietic cell types and whether these mechanisms require uPA production by one cell type and uPAR expression by another remain to be determined.…”