Vasoactive intestinal peptide (VIP), a neuropeptide that is produced by lymphoid as well as neural cells, exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, which acts by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been described to prevent death by septic shock, an acute inflammatory disease with a high mortality. In addition, VIP regulates the expression of co-stimulatory molecules, this being an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that VIP prevents the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Therefore, VIP has been proposed as a promising candidate alternative treatment for acute and chronic inflammatory and autoimmune diseases such as septic shock, arthritis, multiple sclerosis, Crohn disease, or autoimmune diabetes.
The pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the VIP/secretin/glucagon family of peptides, produced by the lymphoid cells, which exerts a wide spectrum of immunological functions controlling the homeostasis of immune system through different receptors expressed in various immunocompetent cells. In the last decade, PACAP has been clearly identified as a potent anti-inflammatory factor that exerts its function by regulating the production of both anti- and proinflammatory mediators. In this sense, PACAP prevents death by septic shock, an acute inflammatory disease with a high mortality. In addition, PACAP regulates the expression of costimulatory molecules, inasmuch as this related to the modulation in the shift from Th1 towards Th2 differentiation. We recently reported that PACAP prevents the deleterious effects of arthritis by downregulating both inflammatory and autoimmune components of the disease. Therefore, PACAP and analogs have been proposed as very promising candidates, alternative to other existing treatments, for treating acute and chronic inflammatory and autoimmune diseases, such as septic shock, arthritis, multiple sclerosis, Crohn's disease, or autoimmune diabetes.
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclaseactivating 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 downregulating 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 acts in vivo as 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 antiinflammatory agents.
Our observations confirm that the proposed anti-inflammatory actions of VIP in murine models also apply to human synovial cells ex vivo. Further studies are encouraged to evaluate the use of VIP as a potential therapy for chronic inflammatory joint diseases.
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