Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages

Abstract

Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by immune cells that can modulate several immune aspects, including the function of cells involved in the inflammatory response, such as macrophages and monocytes. Production and release of cytokines by activated mononuclear phagocytes is an important event in the pathogenesis of ischemia-reperfusion injury. VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon. We have investigated the effects of VIP and PACAP38 on the production of interleukin-6 (IL-6), a proinflammatory cytokine, by endotoxin-activated murine macrophages. Both neuropeptides exhibit a dual effect on the IL-6 production by peritoneal macrophages. Whereas VIP and PACAP inhibit with similar dose-response curves the release of IL-6 from macrophages stimulated with a LPS dose range from 100 pg/mL to 10 g/mL, both neuropeptides enhance IL-6 secretion in unstimulated macrophages and in macrophages stimulated with very low LPS concentrations (1-10 pg/mL). The inhibition on LPS-induced IL-6 production is specific, presumably mediated through a subtype of the PACAP-R. VIP and PACAP regulate the production of IL-6 at a transcriptional level. These results were correlated with an inhibition on both IL-6 expression and release in endotoxemic mice in vivo. These findings support the idea that in the absence of stimulation or in the presence of low doses of LPS, VIP and PACAP could play a role in immune system homeostasis. However, under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of IL-6 in order to reduce inflammation or shock.

Pituitary Adenylate Cyclase-Activating Polypeptide 27 Is a Functional Ligand for Formyl Peptide Receptor-Like 1

“…In monocytes and macrophages, PACAP molecules suppress the production of the proinflammatory cytokines, TNF-␣, IL-6, and IL-12 (6 -8). In contrast, in unstimulated macrophages and astrocytes, PACAP molecules initiate the IL-6 secretion, which induces a proinflammatory response (3)(4)(5). Chemotactic migration events also show this degree of complexity.…”

“…Pituitary Adenylate Cyclase-Activating Polypeptide 27 Is a Functional Ligand for Formyl Peptide Receptor-Like 1 1 T he two pituitary adenylate cyclase-activating polypeptides (PACAPs), 3 PACAP27 and PACAP38, are neuropeptides that belong to the secretin/glucagon/vasoactive intestinal peptide (VIP) family (1). PACAPs are multifunctional peptide hormones that influence diverse biological functions, e.g., the cell cycle, smooth muscle and cardiac muscle relaxation, bone metabolism, and endocrine/paracrine function (2).…”

“…Therefore, we undertook to elucidate PACAP-mediated immune cell functions by investigating the receptor expression pattern. PAC1 has been reported to inhibit IL-6 production in stimulated macrophages, despite its up-regulation of IL-6 secretion in unstimulated macrophages (3,4). VPAC1 has also been reported to participate in PACAP-induced IL-6 secretion in unstimulated macrophages (4).…”

Tuning immune tolerance with vasoactive intestinal peptide: A new therapeutic approach for immune disorders

“…The answer may lie in the fact that VIP exerts most of its effects, in the majority of tissues, via the cAMP/PKA pathway, including the downregulation of inflammatory mediators [12,18,25,33,[35][36][37]66]. Several cAMP-inducing agents have been shown to be potent anti-inflammatory factors [3,8,64].…”

“…Mounting evidence indicates that VIP acts via multiple mechanisms to counter inflammatory factors: a) VIP inhibits phagocytic activity, free radical production, adherence and migration of macrophages [12]; b) VIP reduces the production of inflammatory cytokines (tumor necrosis factor [TNFα], IL-12, IL-6 and IL-1β) and downregulates the expression of inducible nitric oxide synthase and the subsequent release of nitric oxide by macrophages, DCs and microglia [33,[35][36][37]55,66,87]; c) VIP limits the release of various chemokines and impairs signaling through chemokine receptors [18,25,36,53,55,72,95]; d) VIP stimulates the production of antiinflammatory cytokines such as IL-10, TGFβ1 and IL-1Ra [34,87]; e) VIP can decrease the co-stimulatory activity of antigen-presenting cells (APCs) toward antigen-specific T cells by downregulating the expression of the co-stimulatory molecules CD80 and CD86 [38]; and f) by reducing the expression of TLRs and associated molecules [29,46].…”