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

• Published in: Annals of the rheumatic diseases Vol. 66; no. 5; pp. 582 - 588
• Main Authors: Gonzalez-Rey, Elena, Chorny, Alejo, Del Moral, Raimundo G, Varela, Nieves, Delgado, Mario
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.05.2007; BMJ; BMJ Publishing Group LTD; BMJ Group
• Subjects: Animals; Anti-Inflammatory Agents - immunology; Anti-Inflammatory Agents - therapeutic use; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - immunology; Biological and medical sciences; Cell growth; CFA; CIA; CII; collagen type II; Collagen Type II - immunology; collagen-induced arthritis; complete Freund’s adjuvant; cortistatin; CST; Cytokines; Cytokines - drug effects; Cytokines - immunology; Disease Models, Animal; Diseases of the osteoarticular system; DLN; Dose-Response Relationship, Drug; Down-Regulation - immunology; draining lymph nodes; Extended Report; Government agencies; IFN; Immunoglobulins - blood; Inflammation; Inflammatory joint diseases; interferon; interleukin; Medical sciences; Mice; Mice, Inbred DBA; Mortality; Neuropeptides; Neuropeptides - immunology; Neuropeptides - therapeutic use; Neutrophils; PPD; purified protein derivative; Receptors, G-Protein-Coupled - immunology; Receptors, Ghrelin; Receptors, Somatostatin - immunology; rheumatoid arthritis; Rodents; Severity of Illness Index; somatostatin receptors; sst; Synovial Membrane - immunology; Synovial Membrane - pathology; T helper cell type 1; TGF; Th1; Th1 Cells - immunology; TNF; transforming growth factor; Treatment Outcome; tumour necrosis factor; California; Inflammatory joint disease; Treatment; Immunological investigation; Inflammatory arthritis; Diseases of the osteoarticular system; T-Lymphocyte
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.2006.062703

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 β1. 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.