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VASOACTIVE INTESTINAL PEPTIDE (VIP) AND PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) AS MODULATORS OF BOTH INNATE AND ADAPTIVE IMMUNITY

¹ Department of Biological Sciences, Rutgers University, 101 Warren St., Newark, NJ 07102, USA; and ² Departamento Biologia Celular, Facultad de Biologia, Universidad Complutense, Madrid 28040, Spain;

View larger version (35K): [in a new window]   Figure 1. Effects of VIP and PACAP on activated macrophages. VIP or PACAP released in the vicinity of activated macrophages bind to specific receptors (VPAC1, VPAC2, PAC1) and inhibit expression and production of pro-inflammatory agents (TNF, IL-6, nitric oxide [NO], chemokines [CK], and IL-12) and, indirectly, through IL-12, VIP, and PACAP inhibit IFN production from antigen-stimulated Th cells. In contrast, VIP and PACAP up-regulate the production of IL-10, an anti-inflammatory cytokine. VIP and PACAP also inhibit expression of the co-stimulatory molecules B7.1 and B7.2, and the subsequent induction of T-cell proliferation. The in vivo inhibitory effects on pro-inflammatory cytokines and the up-regulation of the anti-inflammatory cytokine IL-10 correlate with the protective effects of VIP and PACAP against septic shock (Delgado et al., 1999f) and in experimental arthritis (Delgado et al., 2001). Macrophage-derived molecules inhibited by VIP/PACAP are boxed in shaded areas, whereas those up-regulated by VIP/PACAP are boxed in clear areas.

View larger version (51K): [in a new window]   Figure 2. Transduction pathways and transcription factors involved in the effects of VIP and PACAP on activated macrophages. (A) Effects on the IFN-induced transduction pathway. VIP/PACAP bind to VPAC1, induce cAMP, and inhibit Jak1/Jak2 phosphorylation, and subsequent STAT1 phosphorylation and binding to the GAS sequence. As a consequence, IRF-1 transcription and synthesis is inhibited, and VIP/PACAP inhibit IRF-1 binding to sequences from both iNOS and IL12p40 genes. (B) Effects on the AP-1 transcription factor. VIP/PACAP bind to the VPAC1 receptor, induce cAMP, and exert two different effects: (a) inhibition of MEKK1 phosphorylation, and subsequent phosphorylation of MEK4, JNK, and c-Jun; and (b) up-regulation of JunB synthesis and nuclear translocation. As a result, the complexes binding to the AP-1 sites in activated macrophages treated with VIP or PACAP contain JunB/c-Fos instead of c-Jun/c-Fos, the transactivating complexes found in LPS-stimulated macrophages. (C) Effects on NFB. VIP/PACAP bind to VPAC1 and initiate two transduction pathways, a cAMP-dependent and a cAMP-independent (unidentified yet) pathway. The cAMP-independent pathway is responsible for the inhibition of the activity of the specific IKK kinase, resulting in the stabilization of the IkB inhibitor. As a result, p65 nuclear translocation and binding to the NFB sequence are inhibited. The cAMP-dependent pathway affects two separate transduction pathways: (a) phosphorylation of CREB (CREB-P), which, upon nuclear translocation, has a high affinity for the co-activator CBP and sequesters CBP, preventing its further interaction with NFB; and (b) inhibition of MEKK1 phosphorylation, subsequent phosphorylation of MEK3/6, p38, and TBP. Non-phosphorylated TBP does not bind efficiently to the TATA box, and does not form an active transactivating complex with CBP and NFB. Reduction in the amounts of nuclear p65, CBP, and phosphorylated TBP inhibits the formation of the conformationally active transactivating complex required for the transcription of most cytokine and chemokine genes. (D) Effects on IL-10 gene expression. VIP/PACAP bind to VPAC1 and induce cAMP, which leads to the phosphorylation of CREB. CREB-P, upon nuclear translocation, binds to the CRE sequence and up-regulates IL-10 gene expression following LPS stimulation.

View larger version (25K): [in a new window]   Figure 3. Effects of VIP/PACAP on Th cell differentiation. Although recent reports indicate that VIP affects dendritic cell (DC) maturation and migration (Delneste et al., 1999; Dunzendorfer et al., 2001), the effects of VIP and PACAP on dendritic cell (DC)–resting Th cell interactions remain to be investigated. VIP/PACAP inhibit IL-2 production and T-cell proliferation following initial exposure to the antigen. VIP/PACAP affect differentiation into effector Th cells, inhibiting Th1 and promoting Th2 differentiation. This effect is exerted through at least two separate pathways: (a) inhibition of IL-12 production (a required Th1 differentiation factor); and (b) posibly, through the up-regulation of macrophage B7.2, but not B7.1, by VIP/PACAP. Generation of memory Th cells requires survival of a small number of activated effectors following apoptosis, which eliminates most effectors at the end of the immune response. VIP/PACAP promote the survival of Th2, but not Th1, effectors, and the generation of long-term memory Th2 cells.