VASOACTIVE-INTESTINAL-PEPTIDE AND PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE MODULATE ENDOTOXIN-INDUCED IL-6 PRODUCTION BY MURINE PERITONEAL-MACROPHAGES

Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by i mmune cells that can modulate several immune aspects, including the fu nction of cells involved in the inflammatory response, such as macroph ages and monocytes. Production and release of cytokines by activated m ononuclear phagocytes is an important event in the pathogenesis of isc hemia-reperfusion injury. VIP has been shown to attenuate the deleteri ous consequences of this pathologic phenomenon. We have investigated t he effects of VIP and PACAP38 on the production of interleukin-6 (IL-6 ), a proinflammatory cytokine, by endotoxin-activated murine macrophag es. Both neuropeptides exhibit a dual effect on the IL-6 production by peritoneal macrophages. Whereas VIP and PACAP inhibit with similar do se-response curves the release of IL-6 from macrophages stimulated wit h a LPS dose range from 100 pg/mL to 10 mu g/mL, both neuropeptides en hance IL-6 secretion in unstimulated macrophages and in macrophages st imulated with very low LPS concentrations (1-10 pg/mL). The inhibition on LPS-induced IL-6 production is specific, presumably mediated throu gh 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 stimulat ion 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 red uce inflammation or shock.