These individual differences in response to each agent highlight the difficulty and limit of treating multifactorial disease by targeting single cytokine or single cell type. Custom peptide synthesis patient tailored therapy might be able toovercome this issue, but good biomarkers to predict treatment responses have not yet been elucidated. Therefore, as described above, biological drugs have limited values. In addition, such drugs may be accompanied by serious side effects. Furthermore, the high cost of these biological drugs may make access to these reagents prohibitive for the general public. Alternative therapeutic options, such as small molecule based drugs, continue to be an important challenge. The involvement phospholipases of prostaglandin pathways in the pathogenesis of arthritis has been shown in animal models by using mice lacking genes, such as cycolooxygenase 2, prostaglandin E synthase, or prostacyclin receptor.
As COX 2 knockout mice normally develop autoreactive T cells in collagen induced arthritis, prostaglandin pathways appear to be involved mainly in the effector phase of arthritis. However, Paclitaxel treatment with celecoxib, a prototype drug belonging to a new generation of highly specific COX 2 inhibitors has been reported to have only mild suppressive effects on animal models of arthritis, and strong inhibition of arthritis was achieved only when mice were treated in the combination of celecoxib with leukotriene inhibitors. In humans, although celecoxib is widely used as an analgesic agent in patients with RA or osteoarthritis, there is no evidence that celecoxib therapy modulates the clinical course of RA. In addition, recently it has been shown that celecoxib enhances TNFa production by RA synovial membrane cultures and human monocytes. Celecoxib has been reported to exhibit COX 2 independent effects, such as tumor growth inhibition and immunomodulation.
Previously, we demonstrated that celecoxib treatment suppressed experimental autoimmune encephalomyelitis in a COX 2 independent manner. We recently developed a trifluoromethyl analogue of celecoxib 3 1Hpyrazol 1 yl]benzenesulfonamide, with 205 fold lower COX 2 inhibitory activity. In studies Clopidogrel using recombinant cell lines, TFM C inhibited secretion of the IL 12 family cytokines, IL 12, p80 and IL 23, through a COX 2 independent, Ca2 dependent mechanism involving chaperone mediated cytokine retention in the endoplasmic reticulum coupled to degradation via the ER stress protein HERP. In the present study, we demonstrate that TFM C inhibits innate immune cells and animal models of arthritis, including CIA and type II collagen antibody induced arthritis, in contrast to the limited inhibitory effect of celecoxib. TFM C suppresses the activation of mast cells in arthritic joints. Moreover, TFM C treatment suppresses the production of inflammatory cytokines by macrophages and leukocyte recruitment. These findings indicate that TFM C may serve as an effective new drug for the treatment of arthritis, including RA. Materials and methods Differentiation and stimulation of U937 cells Human U937 cells were obtained from the American Type Culture Collection and cultured in RPMI 1640 supplemented with 10% FCS. To differentiate U937 cells, 5 × 105 cells were treated with PMA for 24 hours.