cortistatin-14 and Arthritis--Rheumatoid

Cortistatin (CST) is a recently described neuropeptide that shares high homology with somatostatin (somatotropin release-inhibiting factor, SRIF) and binds with high affinity to all somatostatin (sst) receptor subtypes. CST is currently known to have a widespread distribution in many human organs including the immune system. The activities specific to CST may be partially attributable to its binding to the growth hormone secretagogue (GHS)-receptor (GHS-R) and the orphan G-protein-coupled receptor MrgX2. Human immune cells produce CST, whereas macrophage lineage and activated endothelium express sst2, and human lymphocytes express sst3. The human thymus expresses sst1, 2, 3, MrgX2 and almost all immune cells express GHS-R. Moreover, at this very moment promising research with CST in experimental animal models is being performed. On the basis of these promising results, studies aiming to further evaluate the possibilities of CST as a therapeutic agent in human immune-mediated inflammatory diseases are warranted.

Topics: Arthritis, Rheumatoid; Endothelium; Humans; Immune System; Inflammation; Lymphocytes; Macrophages; Nerve Tissue Proteins; Neuropeptides; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Receptors, Neuropeptide; Receptors, Somatostatin; Somatostatin; Thymus Gland

The induction of immune tolerance is critical for the prevention of autoimmunity and the maintenance of immune homeostasis. The identification of factors involved in the maintenance or restoration of such tolerance has become the focus of new therapies for inflammatory and autoimmune diseases. Cortistatin, a recently discovered cyclic neuropeptide related to somatostatin, has emerged as a potential endogenous antiinflammatory factor based on its production by, as well as its binding to, immune cells. Thus, cortistatin has been found to downregulate the inflammatory response mediated by activated macrophages. The present work reviews various recent studies involving different experimental models of sepsis, rheumatoid arthritis and inflammatory bowel disease, demonstrating that cortistatin treatment offers great benefits at both the clinical and pathological levels. These include the downregulation of both inflammatory and Th1-mediated autoimmune disease components and the emergence of regulatory T cells (Treg) that suppress autoreactive T cells, both of which contribute to the restoration of immune tolerance. While many questions need to be resolved, cortistatin appears to be an exciting and promising candidate for the treatment of several chronic inflammatory diseases and autoimmune disorders.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Autoimmune Diseases; Clinical Trials as Topic; Humans; Immunologic Factors; Inflammation; Inflammatory Bowel Diseases; Macrophages; Neuropeptides; Shock, Septic; Th1 Cells

Endothelial dysfunction is the early stage of atherosclerosis, which is typically associated with rheumatoid arthritis (RA), a chronic inflammatory autoimmune disorder. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, is not only an independent predictor for endothelial dysfunction but also a proinflammatory mediator. It has been shown that the level of ADMA was elevated in patients with RA. In the present study, we investigated the potential effect of ADMA on inflammation process in collagen-induced arthritis (CIA) animal model and primary cultured fibroblast-like synoviocytes (FLS) exposed to tumor necrosis factor-α (TNF-α). In CIA rats, the plasma levels of inflammatory cytokines TNF-α, interleukin-1β (IL-1β) and IL-6 were markedly increased, while the plasma levels of ADMA did not increase. The expression of dimethylarginine dimethylohydrolase2 (DDAH2), the key enzyme for ADMA degradation, was markedly reduced in inflamed joint synovium of CIA rats. Moreover, the expression of anti-inflammatory factor cortistatin (CST) was markedly decreased in joint synovium of CIA rats. Treatment of cultured FLS with TNF-α significantly increased the levels of ADMA, and decreased the expression of DDAH2 mRNA and protein accompany with an increase in the levels of IL-1β and IL-6 and a reduction in the expression of CST mRNA and protein, and the effects of TNF-α were abolished by DDAH2 overexpression. Treatment of FLS with ADMA also significantly increased the levels of IL-1β and IL-6, and reduced the expression of CST. These findings suggest that DDAH/ADMA participates in the pathogenesis of RA, and that the effect of DDAH/ADMA may be mediated by CST.

Topics: Amidohydrolases; Animals; Ankle Joint; Arginine; Arthritis, Experimental; Arthritis, Rheumatoid; Cytokines; Male; Neuropeptides; Rats; Rats, Sprague-Dawley; Synovial Membrane