Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on the Reduction of Joint Inflammation in Experimental Rheumatoid Arthritis

Abstract

This study focused on the potential therapeutic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on collagen-induced arthritis (CIA) and on the elucidation of the mechanisms involved. DBA/1J mice with established CIA were treated with various amount of recombinant soluble human TRAIL. The effects of TRAIL on the development and severity of CIA in this DBA/1J mouse model were assessed clinically and histologically, and a detailed investigation was conducted on proinflammatory cytokine and anticollagen-specific antibody levels. Cellular immunity was evaluated by investigating the proliferative responses and cytokine release profiles of splenocytes after TRAIL treatment. TRAIL treatment significantly reduced the severity and incidence of CIA, joint swelling, erythema, and edema. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in joints of TRAIL-treated mice with dose-dependent manner. TRAIL treatment also strongly decreased and/or normalized the productions of proinflammatory cytokines and of anti-collagen-specific antibodies in the sera of CIA mice. Furthermore, in vitro studies with primary splenocytes showed the cytotoxic effect of TRAIL on activated lymphocytes, with reduction of inflammatory cytokine release. These findings show that TRAIL administration is an effective anti-inflammatory treatment that prevents the development and progression of CIA in DBA/1J mice, and they suggest that TRAIL might be considered a potential treatment for human RA.

Selective elimination of pathogenic synovial fluid T-cells from Rheumatoid Arthritis and Juvenile Idiopathic Arthritis by targeted activation of Fas-apoptotic signaling

“…Recent reports indicate that treatment with the pro-apoptotic death ligand TRAIL ameliorates disease activity in animal models of RA [27][28][29]. In another study, TRAIL appeared to inhibit DNA synthesis and cell cycle progression in inflammatory cells, but lacked direct apoptotic activity [46].…”

“…Taken together, these data indicate that the various T H1 subpopulations analyzed are susceptible to treatment with scFvCD7:sFasL, whereas T H2 cell types are largely resistant. (sTRAIL) [27][28][29]. Therefore, we performed a side-by-side comparison of the apoptotic activity of fusion protein scFvCD7:sFasL and scFvCD7:sTRAIL.…”

Trauma patients' elevated tumor necrosis related apoptosis inducing ligand (TRAIL) contributes to increased T cell apoptosis

“…This septic sera factor was not identified but our data suggest elevated plasma TRAIL can increase T cell apoptosis when TSP-1 is concomitantly present. Since TRAIL alone is unable to mediate apoptosis in primary stimulated T cells, an additional serum mediator needs to be involved in mediating the control T cell apoptosis induced by trauma patients’ sera [13, 27, 28]. TSP-1 is increased post-injury and can trigger CD47 (its receptor) on T cells to induce apoptosis [15, 22].…”

Regulatory B cells and advances in transplantation

“…Jin et al. reported that TRAIL‐expressing B cells can inhibit cellular immune responses and inflammatory cell infiltration with reduced proinflammatory cytokine and Ab production in collagen‐induced arthritis mice . Upon engagement with TRAIL receptors on target cells, TRAIL expressed by B cells activates apoptosis inducing signaling cascades, ultimately leading to cell death …”