Vasoactive intestinal peptide (VIP) is an anti-inflammatory immunomodulatory neuropeptide with therapeutic potential demonstrated for collagen-induced arthritis. The aim of this study was to characterise its potential anti-arthritic effect on human monocytes, macrophages, T cells, and rheumatoid arthritis synovial membrane cells. Monocytes, macrophages, and T cells derived from human peripheral blood were treated with VIP and compared with other cAMP-elevating drugs for a range of activating stimuli. Cytokine production was assessed for cell cultures and, in addition, the ability of VIPs to activate cAMP response element binding protein. VIP partially suppressed monocyte- and macrophage-derived tumour necrosis factor α (TNF-α) with no effect on IL-10, whereas VIP fails to regulate IL-10 and TNF-α production by T lymphocytes. No such modulation of cytokine profile was observed for rheumatoid arthritis synovial membrane cells. Elevation of intracellular cAMP, on the other hand, potently suppressed macrophage TNF-α production and modulated T-cell response by inhibiting TNF-α and IFN-γ. VIP's lack of effect on IL-10 and its slight effect on TNF-α results from cAMP being rapidly degraded as the phosphodiesterase IV inhibitor, rolipram, rescues cAMP-dependent activation of cAMP response element binding protein. Interestingly, macrophages stimulated with phorbol 12-myristate 13-acetate/ionomycin displayed an augmented IL-10 response upon addition of dibutyryl cAMP, with corresponding downregulation in TNF-α, suggesting a complex interaction between protein kinase C and protein kinase A in cytokine regulation. In conclusion, VIP may represent an efficaceous anti-arthritic treatment modulating macrophage and T-cell cytokine profiles when used alongside a phosphodiesterase inhibitor.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by the dysregulated expression of many proinflammatory cytokines including tumour necrosis factor α (TNF-α), with increased yet insufficient production of anti-inflammatory cytokines including IL-10. The validation of TNF-α as a therapeutic target in RA has encouraged the investigation of signalling pathways regulating its production by cells relevant to the pathophysiology of this disease. One pathway known to downregulate proinflammatory TNF-α production and, consequently, upregulate the anti-inflammatory cytokine IL-10 is that elicited by the second messenger cAMP. This pathway may therefore represent a good therapeutic target due to its opposing effects on TNF-α and IL-10. Previously, we and others demonstrated that rolipram, a phosphodiesterase (PDE) IV inhibitor, reduced the clinical and histological severity of collagen-induced arthritis (CIA). These studies demonstrated the potential for the cAMP/protein kinase A (PKA) pathway in treatment of autoimmune diseases such as RA.
Another stimulator of the cAMP/PKA pathway whose principle immunomodulatory functions are anti-inflammatory is the vasoactive intestinal peptide (VIP). VIP is a 28-aminoacid neuropeptide belonging to the glucagon/secretin family, found in the nervous system and in the immune system, where it is detected in a variety of cell types including mast cells, neutrophils, and mononuclear cells. The effects of VIP are transduced via three known receptors, VPAC1, VPAC2, and PAC1, all of which are coupled to adenylate cyclase via heterotrimeric G proteins. In vivo, VIP has a therapeutic effect in the CIA mouse model and protects from lipopolysaccharide (LPS) shock by suppression of TNF-α and nuclear factor κB (NF-κB) activation. Furthermore, in vitro studies showed that VIP inhibits the production of proinflammatory factors TNF-α, IL-6, IL-12, chemokines, and nitric oxide (NO) and stimulates the production of the anti-inflammatory cytokine IL-10, most of these effects being apparently mediated through the VPAC1 receptor. In addition, neuropeptides such as VIP have been shown to inhibit activities both of stimulated T cells (VIP being described as a Th2 cytokine), effectively suppressing T helper cell type 1 (Th1) differentiation and of macrophages and to antagonise inflammatory mediators such as histamine, prostaglandin E2, leukotrienes, and neurokinins. The mechanism by which VIP antagonises LPS-induced production of proinflammatory TNF-α and abrogates production of anti-inflammatory IL-10 is suggested to result from a fine balance between cAMP response element DNA binding factors where VIP increases the phosphorylation of PKA-dependent cAMP response element binding protein (CREB) and decreases the phosphorylation of c-Jun N-terminal kinase-dependent c-Jun phosphorylation, without affecting the amount of CRE binding: changes of CRE binding complexes from high c-Jun/low CREB (LPS treated) to low c-Jun/high CREB (VIP treated) leads to an inhibition of TNF-α mRNA expression, whereas the corresponding stimulation in IL-10 gene expression is due to an increase in CRE binding by VIP.
It would appear from these studies that VIP has therapeutic potential based on its ability to ameliorate CIAin mice, this effect possibly mediated by cAMP. However, the effect of VIP on human cells and particularly on RA synovial cells is unknown. Thus the aim of this study was to examine the potential of VIP as a therapeutic agent in chronic inflammatory diseases such as RA by investigating its effects on human macrophages, T cells, and synovial cells all of which play an important role in the pathology of RA and compare the findings with murine VIP data already published.