Anti-epileptic drugs inhibit viability of synoviocytes in vitro

Introduction and objective: The hyperplasia of synovial fibroblasts is considered to be essential for the evolution of joint destruction in rheumatoid arthritis (RA). Previously, we reported that anti-rheumatic drugs, both COX inhibitors and disease-modifying anti-rheumatic drugs inhibit proliferation of synoviocytes in vitro. The presented study investigates the effect of anti-epileptic drugs on the viability and proliferation of synovial fibroblasts in vitro. Methods: Experiments were conducted on human synoviocytes derived from an RA patient and rabbit synoviocytes cell line HIG-82. Cell proliferation and viability were assessed by means of BrdU assay and MTT assay, respectively. The IC50 value (the concentration of drug necessary to induce 50% inhibition) together with confidence limits was calculated. Results: Carbamazepine inhibited proliferation of human fibroblasts and viability of HIG-82 with IC50 values of 86 μM and 82 μM, respectively. Diphenylhydantoin, valproate and phenobarbital inhibited viability of HIG-82 cells with the IC50 values of 110, 500 and 1031 μM, respectively. Conclusion: Based on these findings, it can be suggested that anti-epileptic drugs may have a disease-modifying effect on rheumatoid synovial proliferation

Kynurenic Acid Triggers Firm Arrest of Leukocytes to Vascular Endothelium under Flow Conditions*

Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-γ-induced degradation of tryptophan by indoleamine 2,3-dioxygenase, activates the previously orphaned G protein-coupled receptor, GPR35. This receptor is expressed in immune tissues, although its potential function in immunomodulation remains to be explored. We determined that GPR35 was most highly expressed on human peripheral monocytes. In an in vitro vascular flow model, KYNA triggered the firm arrest of monocytes to both fibronectin and ICAM-1, via β1 integrin- and β2 integrin-mediated mechanisms, respectively. Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a Gi-mediated process. Furthermore, KYNA-triggered adhesion of monocytic cells was reduced by short hairpin RNA-mediated silencing of GPR35. Although GPR35 is expressed at slightly lower levels on neutrophils, KYNA induced firm adhesion of these cells to an ICAM-1-expressing monolayer as well. KYNA also elicited neutrophil shedding of surface L-selectin, another indicator of leukocyte activation. Taken together, these data suggest that KYNA could be an important early mediator of leukocyte recruitment