Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by the presence of inflammatory synovitis accompanied by destruction of joint cartilage and bone. Treatment with vasoactive intestinal peptide (VIP) prevents experimental arthritis in animal models by downregulation of both autoimmune and inflammatory components of the disease. The aim of this study was to characterize the protective effect of VIP on bone erosion in collagen-induced arthritis (CIA) in mice. We have studied the expression of different mediators implicated in bone homeostasis, such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), receptor activator of nuclear factor-κB (RANK), receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), IL-1, IL-4, IL-6, IL-10, IL-11 and IL-17. Circulating cytokine levels were assessed by ELISA and the local expression of mediators were determined by RT-PCR in mRNA extracts from joints. VIP treatment resulted in decreased levels of circulating IL-6, IL-1β and TNFα, and increased levels of IL-4 and IL-10. CIA-mice treated with VIP presented a decrease in mRNA expression of IL-17, IL-11 in the joints. The ratio of RANKL to OPG decreased drastically in the joint after VIP treatment, which correlated with an increase in levels of circulating OPG in CIA mice treated with VIP. In addition, VIP treatment decreased the expression of mRNA for RANK, iNOS and COX-2. To investigate the molecular mechanisms involved, we tested the activity of NFκB and AP-1, two transcriptional factors closely related to joint erosion, by EMSA in synovial cells from CIA mice. VIP treatment in vivo was able to affect the transcriptional activity of both factors. Our data indicate that VIP is a viable candidate for the development of treatments for RA.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two mediators synthesized by immune cells, specially under inflammatory and antigen stimulation conditions. Reports have shown that neuropeptides attenuate the deleterious consequences of septic shock both by down-regulating the production of proinflammatory mediators and by stimulating the production of anti-inflammatory cytokines by activated macrophages. In this study, we used a knockout for the PACAP receptor (PAC1^−/−) to demonstrate an important protective role for PAC1 receptor in endotoxic shock. Moreover, our results indicate that PAC1 receptor actsin vivoas an anti-inflammatory receptor, at least in part, by attenuating lipopolysaccharide (LPS)-induced production of proinflammatory IL-6, which appears to be the main cytokine regulating the expression of the majority of the acute phase protein genes, which are an important deleterious component of septic shock. Besides, our findings point to endogenously produced VIP and PACAP as participants of the natural anti-inflammatory machinery. Because VIP and PACAP are two attractive candidates for the development of therapies against acute and chronic inflammatory diseases, septic shock, and autoimmune diseases, this paper represents a contribution to the understanding of the mechanism of action of these anti-inflammatory agents.

Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability when patients are unsuccessfully treated. Although the specific causes of many rheumatic conditions remain unknown, it is generally accepted that immune mechanisms and/or uncontrolled inflammatory responses are involved in their etiology and symptomatology. In this regard, the bidirectional communication between neuroendocrine and immune system has been demonstrated to provide a homeostatic network that is involved in several pathological conditions. Adipokines represent a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes that act as signal molecules in the neuroendocrine-immune interactions. Adipokines can also be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the joint microenvironment, showing potent modulatory properties on different effector cells in OA and RA pathogenesis. Effects of adiponectin, leptin, resistin and visfatin on local and systemic inflammation are broadly described. However, more recently, other adipokines, such as progranulin, chemerin, lipocalin-2, vaspin, omentin-1 and nesfatin, have been recognized to display immunomodulatory actions in rheumatic diseases. This review highlights the latest relevant findings on the role of the adipokine network in the pathophysiology of OA and RA.