Therapeutic effect of cortistatin on experimental arthritis by downregulating inflammatory and Th1 responses

Abstract

Background: Rheumatoid arthritis is a chronic autoimmune disease of unknown aetiology characterised by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. Aim: To propose a new strategy for the treatment of arthritis based on the administration of cortistatin, a newly discovered neuropeptide with anti-inflammatory actions. Methods: DBA/1J mice with collagen-induced arthritis were treated with cortistatin after the onset of disease, and the clinical score and joint histopathology were evaluated. Inflammatory response was determined by measuring the levels of various inflammatory mediators (cytokines and chemokines) in joints and serum. T helper cell type 1 (Th1)-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with collagen and by assaying the content of serum autoantibodies. Results: Cortistatin treatment significantly reduced the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of cortistatin was associated with a striking reduction in the two deleterious components of the disease-that is, the Th1-driven autoimmune and inflammatory responses. Cortistatin downregulated the production of various inflammatory cytokines and chemokines, decreased the antigen-specific Th1-cell expansion, and induced the production of regulatory cytokines, such as interleukin 10 and transforming growth factor b1. Cortistatin exerted its effects on synovial cells through both somatostatin and ghrelin receptors, showing a higher effect than both peptides protecting against experimental arthritis. Conclusion: This work provides a powerful rationale for the assessment of the efficacy of cortistatin as a novel therapeutic approach to the treatment of rheumatoid arthritis.R heumatoid arthritis (RA) is an autoimmune disease that leads to chronic inflammation in the joints and subsequent destruction of the cartilage and erosion of the bone. Although the contribution of T helper cell type 1 (Th1) responses in RA is not completely understood, several studies in animal models point to a pathogenic role for Th1-derived cytokines. 1 2 Th1 cells reactive to components of the joint infiltrate the synovium, release proinflammatory cytokines and chemokines, and promote macrophage and neutrophil infiltration and activation. Inflammatory mediators, such as cytokines and free radicals, produced by infiltrating inflammatory cells, play a critical role in joint damage. 2 The fact that the inflammatory process in RA is chronic suggests that immune regulation in the joints is disturbed. Available therapies based on immunosuppressive agents inhibit the inflammatory component of RA and have the potential to slow progressive clinical disability by delaying erosions and deformity. 3 However, they neither reduce the relapse rate nor delay disease onset, and because continued treatment is required to maintain a beneficial effect, ...

The role of cortistatin in the human immune system

“…Based on subtype receptor expression in rheumatoid synovium (sst 1-3 ), the recently developed long-acting SRIF analogue SOM-230 which binds to all subtype receptors except sst 4 , may be a promising candidate for therapy in RA. Moreover, Gonzalez-Rey et al show that CST treatment significantly reduces the severity of established collagen-induced arthritis, completely abrogating joint swelling and destruction of cartilage and bone (Gonzalez-Rey et al, 2007). The therapeutic effect of CST is associated with a striking reduction in the two components of disease that are Th1-driven autoimmune and inflammatory responses.…”

“…Cortistatin downregulates the production of various inflammatory cytokines and chemokines, decreases the antigen-specific Th1-cell expansion, and induces the production of regulatory cytokines, such as interleukin-10 and transforming growth factor beta-1. Interestingly, CST exerts its effects on synovial cells through both SRIF and ghrelin receptors (Gonzalez-Rey et al, 2007). SRIF binds only to sst, while CST can also bind to the ghrelin receptor and MrgX2.…”

“…In the same model ghrelin shows also anti-inflammatory effects. CST is exerting its therapeutic effect on collagen induced arthritis partially through the ghrelin receptor, which can be partially reversed by a ghrelin-receptor antagonist (Gonzalez-Rey et al, 2007). In two other models studied by the group of Delgado, an experimental inflammatory bowel disease model and a sepsis model, treatment with CST demonstrates clinical and pathological amelioration of disease (Gonzalez-Rey et al, 2006a;Gonzalez-Rey et al, 2006b).…”

Future clinical prospects in somatostatin/cortistatin/somatostatin receptor field

“…Finally, the effects of CST were investigated in a murine model for rheumatoid arthritis. CST treatment significantly reduced the severity of collagen-induced arthritis, completely abrogating swelling of joints and destruction of cartilage and bone (Gonzalez-Rey et al, 2006a). CST inhibited the T-helper 1 response and production of proinflammatory cytokines as was previously demonstrated in experimental murine models of endotoxemia and inflammatory bowel disease.…”

“…In murine models of lethal endotoxemia it was demonstrated that CST prevented the septic shock-associated histopathology, including inflammatory cell infiltration and multiorgan intravascular disseminated coagulation (Gonzalez-Rey et al, 2006a). CST decreased the levels of cytokines, chemokines and acute phase proteins.…”