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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;
* corresponding author, dganea{at}andromeda.rutgers.edu
(1) Introduction (2) VIP/PACAP Sources in the Immune Organs (3) VIP/PACAP Receptors in Immune Cells (4) Effects of VIP/PACAP on Innate Immunity (A) EFFECTS OF VIP/PACAP ON THE PRODUCTION OF MACROPHAGE-DERIVED CYTOKINES: TRANSDUCTION PATHWAYS AND TRANSCRIPTION FACTORS (B) EFFECTS OF VIP/PACAP ON THE PRODUCTION OF MACROPHAGE-DERIVED CHEMOKINES (C) EFFECTS OF VIP/PACAP ON THE EXPRESSION OF THE CO-STIMULATORY B7 MOLECULES ON RESTING AND ACTIVATED MACROPHAGES (5) Effects of VIP/PACAP on T-cell Function, Survival, and Differentiation (A) VIP/PACAP EFFECTS ON ANTIGEN-INDUCED APOPTOSIS IN T-CELLS (B) VIP/PACAP INHIBIT FASL-MEDIATED CYTOTOXICITY AGAINST DIRECT AND BYSTANDER TARGETS (C) EFFECTS OF VIP/PACAP ON CD4 T-CELL DIFFERENTIATION (6) Conclusions REFERENCES
| Abstract |
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B, CREB, c-Jun, JunB, and IRF-1. The in vivo administration of VIP/PACAP results in a similar pattern of cytokine and chemokine modulation, which presumably mediates the protective effect of VIP/PACAP in septic shock. In addition, VIP/PACAP reduce the expression of the co-stimulatory molecules B7.1/B7.2, and the subsequent stimulatory activity of macrophages for T-helper cells. In T-cells expressing specific VIP/PACAP receptors, VIP and PACAP inhibit the expression of FasL through effects on NFB, NFAT, and Egr2/3. The reduction of FasL expression has several biological consequences: inhibition of antigen-induced cell death in CD4 T-cells, inhibition of the FasL-mediated cytotoxicity of CD8 and CD4 effectors against direct and bystander targets, and promotion of long-term memory Th2 cells, through a positive effect on the survival of Th2, but not Th1, effectors. The various biological effects of VIP and PACAP are discussed within the range of a general anti-inflammatory model. Key words. Neuropeptides, VIP, PACAP, macrophages, T-cell apoptosis, T-cell cytotoxicity, T-cell differentiation
| (1) Introduction |
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The neuropeptides released within the lymphoid microenvironment and the corresponding neuropeptide receptors on immune cells represent the framework for neuropeptides mediating neuroimmune interactions. Although the list of immunomodulatory neuropeptides/neurotransmitters grows at a steady pace, here we review only the effects of VIP and PACAP, two of the best-studied immunoregulatory neuropeptides. The prominent role of VIP and PACAP in immunoregulation is reflected by the number of recent reviews related to this subject (Pozo et al., 2000; Ganea and Delgado, 2001a,b; Gomariz et al., 2001). Here, we focus on the most recent developments regarding the effects of VIP/PACAP on innate and adaptive immunity, particularly on macrophage activation and T-cell differentiation.
| (2) VIP/PACAP Sources in the Immune Organs |
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In addition, immune cells themselves express VIP at both mRNA and protein levels, and stimulators of immune cells such as LPS, cytokines, ConA, or anti-TCR antibodies act as inducers of VIP release (reviewed in Gomariz et al., 2001). We reported recently that VIP is expressed and released from Th2, but not Th1 cells, upon specific antigen stimulation, both in vivo and in vitro (Delgado and Ganea, 2001a). These results indicate that, similar to other neuropeptides, VIP and presumably PACAP are released in the lymphoid organs from two separate sources, the innervation and the immune cells. The challenge remains to identify the factors that control neuronal or immune release of VIP/PACAP during an inflammatory response and to characterize the molecular mechanisms involved.
| (3) VIP/PACAP Receptors in Immune Cells |
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T-lymphocytes express VPAC1 and VPAC2, but not PAC1 (Delgado et al., 1996; Johnson et al., 1996; Xia et al., 1996; Kaltreider et al., 1997; Jiang et al., 1998; Busto et al., 2000). Induction of VPAC2 expression during T-cell activation and differentiation was suggested by several studies (Delgado et al., 1996; Metwali et al., 2000) and by the fact that several fully differentiated T-cell lines express only VPAC2 (Xin et al., 1997; Delgado and Ganea, 2000a). Recently, quantitative real-time RT-PCR studies indicated that VPAC1 is down-regulated and VPAC2 slightly up-regulated following stimulation of human blood T-cells (Lara-Marquez et al., 2001), and that VPAC2 is significantly up-regulated in murine CD4+ T-cells following activation with anti-CD3 and anti-CD28 Abs (Voice et al., 2001).
Whether the various receptors mediate different functions remains to be established. The inhibition of cytokine production by freshly activated T-cells appears to be equally mediated by VPAC1 and VPAC2 (Jiang et al., 1998). However, VPAC2, but not VPAC1, transduces human T-cell chemotaxis (Xia et al., 1996; Goetzl et al., 1998), and VPAC2 mediates the VIP-enhanced conversion of thymocytes into CD4+8- T-cells (Pankhaniya et al., 1998). In macrophages, most of the VIP/PACAP effects appear to be mediated by VPAC1, with the exception of the IL-6 inhibition, which is mediated by PAC1 (reviewed in Delgado et al., 1999b).
| (4) Effects of VIP/PACAP on Innate Immunity |
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(A) EFFECTS OF VIP/PACAP ON THE PRODUCTION OF MACROPHAGE-DERIVED CYTOKINES: TRANSDUCTION PATHWAYS AND TRANSCRIPTION FACTORS
Macrophages initiate the inflammatory response through the secretion of inflammatory cytokines and the production of reactive oxygen and nitrogen intermediates. Microbial products such as LPS induce macrophages to secrete several pro-inflammatory products such as tumor necrosis factor (TNF
), interleukin-12 (IL-12), interleukin 1 (IL-1), interleukin 6 (IL-6), and nitric oxide (NO), followed by the secretion of the anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor beta (TGFß) (Laskin and Pendino, 1995). Although beneficial in host defense, a sustained production of pro-inflammatory agents has serious pathological consequences (Van Snick, 1990; Vassalli, 1992; Evans, 1995). The balance between pro- and anti-inflammatory factors plays an essential role in the successful control of inflammation. Regulatory molecules called "macrophage deactivating factors" have received considerable interest lately. In addition to the anti-inflammatory cytokines IL-10, IL-11, TGFß, and IL-13 (Fiorentino et al., 1991; Trepicchio et al., 1996; Muchamuel et al., 1997; Tsunawaki et al., 1998), neuropeptides such as VIP, PACAP, CGRP, somatostatin, and melanocyte-stimulating hormone (MSH) also function as macrophage-deactivating factors (reviewed in Ganea and Delgado, 2001a). VIP/PACAP inhibit the in vitro and in vivo production of the pro-inflammatory cytokines TNF{alpha}, IL-6, IL-12, and of nitric oxide, and stimulate the production of the anti-inflammatory cytokine IL-10 (Dewit et al., 1998; Martinez et al., 1998; Xin and Sriram, 1998; Delgado et al., 1999a,cde) (Fig. 1
). In addition, VIP/PACAP exert a protective effect in vivo in models of septic shock. The protective effect correlates with the inhibition of endogenous pro-inflammatory cytokines and is mediated through the VPAC1 receptor (Delgado et al., 1999f, 2000).
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, IL-12, and iNOS, and in the stimulation of IL-10 (Delgado et al., 1998, 1999d,e; Delgado and Ganea, 1999). However, except for IL-10, two pathways, a cAMP-dependent and a cAMP-independent pathway, appear to be involved in the inhibitory effects of VIP/PACAP. The effects of VIP/PACAP on both macrophage-derived cytokines and NO are exerted at the transcriptional level through the regulation of several transcription factors. In the case of TNF, iNOS, and IL-12p40 inhibition, the cAMP-independent pathway leads to the reduction in NFB binding (Delgado et al., 1998, 1999d; Delgado and Ganea, 1999). In addition, the cAMP-dependent pathway mediates changes in the CRE-binding complex from highc-Jun/lowCREB to lowc-Jun/highCREB for the TNF promoter (Delgado et al., 1998), inhibition of IRF-1 binding for the iNOS and IL-12p40 promoters (Delgado et al., 1999d; Delgado and Ganea, 1999), and changes in the composition of the AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos with subsequent reduction in AP-1 binding to the TNF{alpha} promoter (Delgado and Ganea, 2000b). The VIP/PACAP increase in IL-10 gene transcription is mediated entirely through an increase in cAMP-dependent CREB binding (Delgado et al., 1999e).
Some of the detailed pathways leading from VPAC1 to gene transactivation have been elucidated (Figs. 2A-2D). Reduction in IRF-1 binding and synthesis is mediated through the inhibition of IFN
-induced Jak1/2-STAT1 phosphorylation (Fig. 2A); although the step(s) between cAMP induction and inhibition of Jak1/2 phosphorylation are not known, we eliminated the involvement of SOCS1 and 3 (Delgado and Ganea, 2000c). Changes in the composition of the AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos, with a subsequent decrease in AP-1 binding, are mediated through the inhibition of the MEKK1/MEK4/JNK pathway, which leads to a reduction in c-Jun phosphorylation and a direct, positive effect on JunB synthesis (Delgado and Ganea, 2000b) (Fig. 2B). The VIP/PACAP decrease in NFB binding which affects numerous genes involved in the inflammatory response (cytokines, chemokines, iNOS) is due to a more complex mechanism. The cAMP-independent pathway results in the inhibition of IB phosphorylation, and its subsequent stabilization. Due to the prolonged presence of this inhibitor, p65 (an essential component of the NFB transactivating complex) is retained in the cytoplasm. The VIP/PACAP effect on IkB phosphorylation is mediated through the inhibition of IKK, the IkB-specific kinase (Delgado and Ganea, 2001b) (Fig. 2C). For maximal transactivation, NF{kappa}B is further complexed to co-activators such as CBP (the CREB-binding protein) and phosphorylated TBP (the TATA-box binding protein) (Yang et al., 1996). VIP/PACAP affect both these proteins in a cAMP-dependent manner. First, through the increase in CREB phosphorylation, CBP is sequestered by nuclear phosphorylated CREB, instead of binding to p65 (Delgado and Ganea, 2001b) (Fig. 2C). Second, through the inhibition of the MEKK1/MEK3-6/p38 pathway, TBP phosphorylation is inhibited, leading to a decrease in TBP binding to both DNA and p65 (Delgado and Ganea, 2001b) (Fig. 2C). Finally, increases in CREB phosphorylation lead to increased CREB binding to the IL-10 promoter and activation of gene transcription (Delgado et al., 1999e) (Fig. 2D).
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, MIP-1ß, MCP-1, and Rantes), in vivo and in vitro. The inhibition is mediated by VPAC1 and correlates with a reduction in NF{kappa}B binding and transactivating activity (Delgado and Ganea, 2001c). The two CXC chemokines MIP-2 and IL-8 function as chemoattractants for neutrophils, whereas the CC chemokines attract monocytes/macrophages and T-cells. Accordingly, i.p. administration of VIP or PACAP in a model of acute peritonitis led to a significant reduction in the recruitment of neutrophils (from 12 to 24 hrs), and of macrophages and lymphocytes (from 24 to 48 hrs) in the peritoneal cavity (Delgado and Ganea, 2001c). The possibility that neuropeptides, particularly VIP and PACAP, might modulate the expression of not only chemokines but also chemokine receptors opens new territories in neuroimmunomodulation, since differences in chemokine receptors impose the different migratory patterns of immature vs. mature dendritic cells, and of Th1 vs. Th2 cells (Sallusto et al., 1998; D'Amico et al., 2000; Sozzani et al., 2000; Zlotnik and Yoshie, 2000). Therefore, neuropeptides might be active participants in the maturation and function of dendritic cells, and in the differential development of Th1 and/or Th2 effector cells.
(C) EFFECTS OF VIP/PACAP ON THE EXPRESSION OF THE CO-STIMULATORY B7 MOLECULES ON RESTING AND ACTIVATED MACROPHAGES
In addition to innate immunity, macrophages also participate in adaptive immunity as antigen-presenting cells. To activate T-cells, macrophages have to provide a second, co-stimulatory signal, in addition to the MHC class II/antigen complex recognized by the specific T-cell receptor. Among the co-stimulatory molecules, B7.1 and B7.2 play major roles. In macrophages, B7.1 and B7.2 are expressed only following activation, with B7.2 being induced earlier and at higher levels than B7.1 (Lenschow et al., 1996).
VIP and PACAP are among the endogenous factors that regulate B7 expression in macrophages. Interestingly, the two neuropeptides affect B7 expression in resting and activated macrophages in an opposite manner. In resting macrophages, VIP/PACAP up-regulate B7.2, but not B7.1, expression at mRNA and protein levels, both in vivo and in vitro. In contrast, in LPS/IFN-activated macrophages, VIP/PACAP down-regulate both B7.1 and B7.2 expression (Delgado et al., 1999g). The effects of VIP/PACAP on B7 expression correlate with effects on the stimulatory activity for T-cells (Delgado et al., 1999g). The inhibition of B7.1/B7.2 expression in activated macrophages is in perfect agreement with the accepted role of VIP and PACAP as endogenous anti-inflammatory agents. Moreover, since VIP/PACAP affect B7 but not MHC class II expression (Delgado et al., 1999g), the neuropeptides could actually contribute to peripheral tolerance by inducing T-cell anergy. In contrast, the up-regulation of B7.2 in unstimulated macrophages might represent one of the mechanisms by which VIP/PACAP support Th2 differentiation, which is discussed below.
| (5) Effects of VIP/PACAP on T-cell Function, Survival, and Differentiation |
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(A) VIP/PACAP EFFECTS ON ANTIGEN-INDUCED APOPTOSIS IN T-CELLS
Following initial TCR engagement, antigen-specific CD4 T-cells enter a proliferative stage and differentiate into clones of antigen-specific effector T-cells. The termination of an immune response requires the elimination of the vast majority of antigen-specific T-cells through apoptosis. Although during initial activation T-cells are apoptosis-resistant, cycling T-cells become highly susceptible to apoptosis. Two different types of apoptosis, passive and active, eliminate activated T-cells. In the absence of further antigenic stimulation, the cycling T-cells undergo passive apoptosis, due to withdrawal of growth factors. However, if the antigen persists, the cycling cells are eliminated through active apoptosis, or antigen-induced cell death (AICD), upon TCR re-engagement (reviewed in Lenardo et al., 1999).
Although studies in the CNS showed that VIP and PACAP act as neuronal survival factors in various injury conditions (Uchida et al., 1996>; Gressens, 1999; Reglodi et al., 2000; Gozes and Brenneman, 2000), the expectation in the immune system was that VIP/PACAP would promote lymphocyte apoptosis, based on their general anti-inflammatory role. However, contrary to this expectation, VIP and PACAP protect activated CD4 T-cells against AICD both in vitro and in vivo (Delgado and Ganea, 2000a). CD4 T-cells undergo AICD primarily through Fas/Fas ligand (FasL) interactions (Alderson et al., 1995; Ju et al., 1995). Fas is expressed constitutively on CD4 T-cells and up-regulated following activation, whereas FasL expression is induced only following TCR re-stimulation (Suda et al., 1995). The VIP/PACAP protection against AICD is actually the result of an inhibitory effect on FasL expression in the re-stimulated CD4 T-cells (Delgado and Ganea, 2000a). The inhibition of FasL expression is mediated through effects on several transcription factors, i.e., NFB, NF-ATp, and Egr2,3 (Delgado and Ganea, 2001d). Similar to their effect in macrophages, VIP/PACAP stabilize IkB and prevent p65 nuclear translocation in T-cells. In addition, VIP/PACAP inhibit NF-ATp nuclear translocation in a calcineurin-independent manner, and prevent the expression of Egr2 and 3, presumably indirectly, through the inhibition of NF-ATp nuclear translocation. In contrast to macrophages, where the effects on NFB are mostly cAMP-independent, in T-cells cAMP functions as the secondary messenger in affecting all three transcription factors (NF{kappa}B, NFAT, Egr2/3) (Delgado and Ganea, 2001d).
The different subsets of effector Th cells play different roles in the immune response, with Th1 being primarily involved in cell-mediated immunity, and Th2 in humoral immunity. The two subsets appear to differ also in terms of susceptibility to AICD, with Th2 cells being more resistant to apoptosis (Varadhachary et al., 1997; Zhang et al., 1997). Whether VIP and PACAP affect AICD preferentially in one of the Th subsets remains to be determined. Recent results from our laboratory suggest that indeed VIP/PACAP protect Th2 cells preferentially, and that this protection correlates with the inhibition of FasL expression (Delgado and Ganea, submitted).
(B) VIP/PACAP INHIBIT FASL-MEDIATED CYTOTOXICITY AGAINST DIRECT AND BYSTANDER TARGETS
FasL/Fas interactions are involved not only in CD4 T apoptosis, but also in cytotoxicity against Fas-bearing targets. Cytotoxic CD8 T-cells (CTL) kill targets through a calcium-dependent, perforin/granzyme-mediated, and through a calcium-independent, FasL-mediated mechanism (Berke, 1995). VIP and PACAP do not affect the perforin/granzyme-mediated cytotoxicity, but inhibit drastically the FasL-mediated lysis of both allogeneic and syngeneic Fas-bearing targets. VIP/PACAP inhibit the FasL-mediated cytotoxicity by preventing FasL expression on the cytotoxic T-cells both in vivo and in vitro (Delgado and Ganea, 2000d).
CD4 T effector cells also express cytotoxic activity. However, in contrast to the CD8 CTLs, the CD4 lytic effectors kill targets only through FasL/Fas-mediated interactions (Ju et al., 1994; Stalder et al., 1994). Antigen-presenting cells (APC) activate CD4 T-cells in a MHC II-restricted manner, leading to the up-regulation of FasL, which then enables the CD4 T-cells to lyse both cognate APCs (direct targets) and neighboring Fas-bearing cells (bystander targets) in an antigen-independent and MHC-nonrestricted manner (Wang et al., 1996; Smyth, 1997). VIP and PACAP inhibit FasL expression in allogeneic and antigen-specific CD4 effectors generated in vivo, and their cytotoxicity for both direct and bystander targets (Delgado and Ganea, 2001e). The elimination of activated APCs removes potentially harmful cells after the completion of an immune response, and therefore represents a required mechanism for the maintenance of immune homeostasis. However, bystander killing results in collateral damage, particularly relevant for tissues with limited MHC II expression, such as the brain. In experimental allergic encephalomyelitis (EAE), myelin-specific CD4 T effectors contribute to the pathology, through lysis of antigen-non-specific targets (Thilenius et al., 1999). Similar mechanisms may be responsible for tissue damage in other autoimmune diseases as well (De Maria and Testi, 1998). In this respect, endogenous agents such as VIP and PACAP, capable of down-regulating FasL expression on T-cells, may be important in the control of FasL/Fas-mediated lysis of innocent bystanders, particularly in immune privileged organs such as the brain and the anterior chamber of the eye, where these neuropeptides are abundant.
(C) EFFECTS OF VIP/PACAP ON CD4 T-CELL DIFFERENTIATION
Following antigenic stimulation, CD4 T-cells differentiate into Th1 and Th2 effector cells, characterized by specific cytokine profiles and functions. Determining factors for the differentiation include the nature of the APC, the nature and amount of antigen, and the genetic background of the host, with the cytokine microenvironment as the dominant factor (reviewed in O'Garra, 1998). Among cytokines, IL-12 and IL-4 appear to be the determinant factors for Th1 and Th2 differentiation, respectively. The possible role of neuropeptides in Th1/Th2 differentiation is just beginning to be investigated.
VIP and PACAP induce Th2 responses in vivo and in vitro (Delgado et al., 1999h). Macrophages treated in vitro with VIP or PACAP gain the ability to induce Th2-type cytokines (IL-4 and IL-5) and inhibit Th1-type cytokines (IFN, IL-2) in Ag-primed CD4 T-cells. In vivo administration of VIP or PACAP in Ag-immunized mice results in a decreased number of IFN{gamma}-secreting cells and an increased number of IL-4-secreting cells (Delgado et al., 1999h). The initial observation of a Th2 bias by VIP/PACAP in normal mice has been confirmed and extended by two elegant studies with VPAC2 transgenic and knockout mice (Voice et al., 2001, and Goetzl et al., 2001, respectively). The two models present opposite phenotypes. The transgenic mice constitutively expressing VPAC2 in CD4+ T-cells produce significantly more Th2 than Th1 cytokines, have high levels of IgE and eosinophils, and develop cutaneous allergic reactions. In contrast, in VPAC2-deficient mice, T-cell activation results in the production of significantly more Th1 than Th2 cytokines, leading to enhanced delayed-type hypersensitivity and depressed cutaneous anaphylactic reaction.
There are several possible non-excluding mechanisms for the VIP/PACAP bias toward Th2 (Fig. 3). Inhibition of macrophage IL-12 production by VIP and PACAP is one possibility. Since IL-4 dominates IL-12, driving naïve CD4 T-cells toward the Th2 phenotype (O'Garra, 1998), a reduction in IL-12 by VIP/PACAP, even in the absence of an effect on IL-4, will result in Th2 differentiation. A second possibility is up-regulation of B7.2 expression on macrophages by VIP/PACAP. Although the role of B7.1 and B7.2 in selectively activating Th1 or Th2-type responses is controversial, several disease models suggest a role for B7.2 in promoting Th2 differentiation (Kuchroo et al., 1995; Keany-Myers et al., 1998; Larche et al., 1998). Finally, a very recent study from our laboratory indicates that VIP and PACAP support Th2, but not Th1, proliferation in vitro, and promote the generation of memory Th2 cells in vivo. These effects correlate with a reduction in FasL expression and inhibition of apoptosis in Th2, but not Th1, cells (Delgado and Ganea, submitted).
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| (6) Conclusions |
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, IL-6, IL-12) by activated macrophages; (2) by up-regulation of IL-10 production (a potent anti-inflammatory cytokine); (3) by inhibition of B7.1/B7.2 expression in activated macrophages and subsequent inhibition of their stimulatory activity for antigen-specific T-cells; (4) by inhibition of IL-2 production and T-cell proliferation; (5) by inhibition of Th1 responses (reduction in both the amounts of Th1 cytokines and the number of cytokine-producing Th1 cells); and (6) by inhibition of FasL/Fas-mediated cytotoxicity of CD8 and CD4 T-cells against direct and bystander targets. In contrast to these well-defined anti-inflammatory functions, VIP and PACAP support the generation and long-term survival of Th2 cells, representing the first neuropeptides with a possible role in the generation of memory Th2 cells. In immune privileged sites such as the brain and the anterior chamber of the eye, this might be one of the most important physiological functions of VIP and PACAP, since the state of immune deviation depends on regulatory cells whose development requires Th2 cytokines.
| Acknowledgments |
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| REFERENCES |
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Allescher HD, Kurjak M, Huber A, Trudrung P, Schusdziarra V (1996). Regulation of VIP release from rat enteric nerve terminals: evidence for a stimulatory effect of NO. Am J Physiol 271:G568–G574.
Bellinger DL, Lorton D, Romano TD, Olschowka JA, Felten SY, Felten DL (1990). Neuropeptide innervation of lymphoid organs. Ann NY Acad Sci 594:17–33.[Medline]
Berke G (1995). The CTL kiss of death. Cell 81:9–12.[Medline]
Bondesson L, Norolind K, Liden S, Gafvelin G, Theodorsson E, Mutt V (1991). Dual effects of vasoactive intestinal peptide (VIP) on leucocyte migration. Acta Physiol Scand 141:477–481.[Medline]
Brouxhon SM, Prasad AV, Joseph SA, Felten DL, Bellinger DL (1998). Localization of corticotropin-releasing factor in primary and secondary lymphoid organs of the rat. Brain Behav Immun 12:107–122.[Medline]
Busto R, Carrero I, Bodega G, Zapatero J, Prieto JC (2000). Immunohistochemical and immunochemical evidence for expression of human lung PACAP/VIP receptors. Ann NY Acad Sci 921:308–311.[Medline]
D'Amico GD, Frascaroli G, Bianchi G, Transidico P, Doni A, Vecchi A, et al. (2000). Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys. Nat Immunol 1:387–391.[Medline]
De Maria R, Testi R (1998). Fas-FasL interactions: a common pathogenic mechanism in organ-specific autoimmunity. Immunol Today 19:121–125.[Medline]
Delgado M, Ganea D (1999). Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit IL-12 transcription by regulating NFB and Ets activation. J Biol Chem 274:31930–31940.
Delgado M, Ganea D (2000a). Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit T cell-mediated cytotoxicity by inhibiting Fas ligand expression. J Immunol 165:114–123.
Delgado M, Ganea D (2000b). VIP and PACAP inhibit antigen-induced apoptosis of mature T lymphocytes by inhibiting FasL expression. J Immunol 164:1200–1210.
Delgado M, Ganea D (2000c). Inhibition of IFN-induced Jak1-STAT1 activation in macrophages by VIP and PACAP. J Immunol 165:3051–3057.
Delgado M, Ganea D (2000d). VIP and PACAP inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages. J Neuroimmunol 110:97–105.[Medline]
Delgado M, Ganea D (2001a). Inhibition of endotoxin-induced macrophage chemokine production by VIP and PACAP in vitro and in vivo. J Immunol 167:966–975.
Delgado M, Ganea D (2001b). Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit expression of Fas ligand in activated T lymphocytes by regulating c-Myc, NFB, NF-AT, and early growth factors 2/3.J Immunol166:1028–1040.
Delgado M, Ganea D (2001c). Cutting edge: is vasoactive intestinal peptide a type 2 cytokine? J Immunol166:2907–2912.
Delgado M, Ganea D (2001d). VIP and PACAP inhibit NFB-dependent gene activation at multiple levels in the human monocytic cell line THP-1. J Biol Chem 276:369–380.
Delgado M, Ganea D (2001e). VIP and PACAP inhibit Fas ligand-mediated bystander lysis by CD4+ T cells. J Neuroimmunol 112:78–88.[Medline]
Delgado M, Martinez C, Johnson MC, Gomariz RP, Ganea D (1996). Differential expression of vasoactive intestinal peptide receptors 1 and 2 (VIP-R1 and VIP-R2) mRNA in murine lymphocytes. J Neuroimmunol 68:27–38.[Medline]
Delgado M, Munoz-Elias EJ, Kan Y, Gozes I, Fridkin M, Brenneman DE, et al. (1998). Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit TNF transcriptional activation by regulating NF-kB and CREB/c-Jun. J Biol Chem 273:31427–31436.
Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D (1999a). VIP and PACAP inhibit IL-12 production in LPS-stimulated macrophages. Subsequent effect on IFN synthesis by T-cells. J Neuroimmunol 96:167–181.[Medline]
Delgado M, Munoz-Elias EJ, Martinez C, Gomariz RP, Ganea D (1999b). VIP and PACAP38 modulate cytokine and nitric oxide production in peritoneal macrophages and macrophage cell lines. Ann NY Acad Sci 897:401–410.[Medline]
Delgado M, Martinez C, Pozo D, Calvo JR, Leceta J, Ganea D, et al. (1999c). Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) protect mice from lethal endotoxemia through the inhibition of TNF and IL-6. J Immunol 162:1200–1205.
Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D (1999d). Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: in vitro and in vivo studies. J Immunol 162:1707–1716.
Delgado M, Pozo D, Martinez C, Leceta J, Calvo JR, Ganea D, et al. (1999e). Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF production by macrophages: in vitro and in vivo studies. J Immunol 162:2358–2367.
Delgado M, Leceta J, Gomariz RP, Ganea D (1999f). VIP and PACAP stimulate the induction of Th2 responses by upregulating B7.2 expression. J Immunol163:3629–3635.
Delgado M, Sun W, Leceta J, Ganea D (1999g). VIP and PACAP differentially regulate the costimulatory activity of resting and activated macrophages through the modulation of B7.1 and B7.2 expression. J Immunol163:4213–4223.
Delgado M, Munoz-Elias EJ, Gomariz RP, Ganea D (1999h). VIP and PACAP prevent inducible nitric oxide synthase transcription in macrophages by inhibiting NF-kB and interferon regulatory factor 1 activation. J Immunol162:4685–4696.
Delgado M, Gomariz RP, Martinez C, Abad C, Leceta J (2000). Anti-inflammatory properties of the type 1 and type 2 vasoactive intestinal receptors: role in lethal endotoxic shock. Eur J Immunol30:3236–3246.[Medline]
Delgado M, Abad C, Martinez C, Leceta J, Gomariz RP (2001). Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med 7:563–568.[Medline]
Delneste Y, Harbault N, Galea B, Magistrelli G, Bazin I, Bonnefoy JY, et al. (1999). Vasoactive intestinal peptide synergizes with TNF-alpha in inducing human dendritic cell maturation. J Immunol 163:3071–3075.
Dewit D, Gourlet P, Amraoui Z, Vertongen P, Willems F, Robberecht P, et al. (1998). The vasoactive intestinal peptide analogue RO25-1553 inhibits the production of TNF and IL-12 by LPS-activated monocytes. Immunol Lett 60:57–60.[Medline]
Dey RD, Shannon WA, Said SI (1981). Localization of VIP-immunoreactive nerves in airways and pulmonary vessels of dogs, cats, and human subjects. Cell Tissue Res 220:231–238.[Medline]
Dunzendorfer S, Kaser A, Meierhofer C, Tilg H, Wiedermann CJ (2001). Cutting edge: peripheral neuropeptides attract immature and arrest mature blood-derived dendritic cells. J Immunol 166:2167–2172.
Evans CH (1995). Nitric oxide: what role does it play in inflammation and tissue destruction? Agents Actions 47:107–116.
Felten DL, Felten SY, Bellinger DL, Carlson SL, Ackerman KD, Madden KS, et al. (1987). Noradrenergic sympathetic neural interactions with the immune system: structure and function. Immunol Rev 100:225–260.[Medline]
Felten DL, Felten SY, Bellinger DL, Lorton D (1992). Noradrenergic and peptidergic innervation of secondary lymphoid organs: role in experimental rheumatoid arthritis. Eur J Clin Invest 22(Suppl) 1:37–41.
Fink T, Weihe E (1988). Multiple neuropeptides in nerves supplying mammalian lymph nodes: messenger candidates for sensory and autonomic neuroimmunomodulation. Neurosci Lett 90:39–54.[Medline]
Fiorentino DF, Zlotnik A, Mossman TR, Howard M, O'Garra A (1991). Interleukin-10 inhibits cytokine production by activated macrophages. J Immunol 147:3815–3822.[Abstract]
Ganea D, Delgado M (2001a). Inhibitory neuropeptide receptors on macrophages. Microbes Infect 3:141–147.[Medline]
Ganea D, Delgado M (2001b). Neuropeptides as modulators of macrophage functions. Regulation of cytokine production and antigen presentation by VIP and PACAP. Arch Immunol Ther Exp 49:101–110.
Goetzl EJ, Kodama KT, Turck DW, Schiogolev AS, Sreedharan SP (1989). Unique pattern of cleavage of VIP by human lymphocytes. Immunology 66:554–558.[Medline]
Goetzl EJ, Pankhaniya RR, Gaufo GO, Mu Y, Xia M, Sreedharan SP (1998). Selectivity of effects of vasoactive intestinal peptide on macrophages and lymphocytes in compartmental immune responses. Ann NY Acad Sci840:540–550.[Medline]
Goetzl EJ, Voice JK, Shen S, Dorsam G, Kong Y, West KM, et al. (2001). Enhanced delayed-type hypersensitivity and diminished immediate-type hypersensitivity in mice lacking the inducible VPAC2 receptor for vasoactive intestinal peptide. Proc Natl Acad Sci USA 98:13854–13859.
Gomariz RP, Martinez C, Abad C, Leceta J, Delgado M (2001). Immunology of VIP: a review and therapeutical perspectives. Curr Pharmacol Design 7:89–111.[Medline]
Gozes I, Brenneman DE (2000). A new concept in the pharmacology of neuroprotection. J Mol Neurosci 14:61–68.[Medline]
Gressens P (1999). VIP neuroprotection against excitotoxic lesions of the developing mouse brain. Ann NY Acad Sci 897:109–124.[Medline]
Grider JR, Jin J-G (1993). Vasoactive intestinal peptide release and L-citrulline production from isolated ganglia of the myenteric plexus: evidence for regulation of vasoactive intestinal peptide release by nitric oxide. Neuroscience 54:521–526.[Medline]
Harling-Berg CJ, Pak JT, Knopf PM (1999). Role of cervical lymphotics in the Th2-type hierarchy of CNS immune regulation. J Neuroimmunol 101:111–127.[Medline]
Harmar A, Arimura A, Gozes I, Journot L, Laburthe M, Pisegna JR, et al. (1998). Nomenclature of receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP). Pharmacol Rev 50:625–627.
Ichikawa S, Sreedharan SP, Goetzl EJ, Owen RL (1994). Immunohistochemical localization of peptidergic nerve fibers and neuropeptide receptors in Peyer's patches of the cat ileum. Regul Peptides 54:385–395.[Medline]
Jiang X, Wang H-Y, Yu J, Ganea D (1998). VIP1 and VIP2 receptors but not PVR1 mediate the effect of VIP/PACAP on cytokine production in T lymhpocytes. Ann NY Acad Sci 865:397–407.[Medline]
Johnson MC, McCormack RJ, Delgado M, Martinez C, Ganea D (1996). Murine T-lymphocytes express vasoactive intestinal peptide receptor 1 (VIP-R1) mRNA. J Neuroimmunol 68:109–119.[Medline]
Johnston JA, Taub DD, Lloyd AR, Conlon K, Oppenheim JJ, Kevlin DJ (1994). Human T lymphocyte chemotaxis and adhesion induced by vasoactive intestinal peptide. J Immunol 153:1762–1768.[Abstract]
Ju ST, Panka DJ, Cui H, Ettinger R, El-Khatib M, Sherr DH, et al. (1995). Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373:444–448.[Medline]
Kaltreider HB, Ichikawa S, Byrd PK, Ingram DA, Kishiyama JI, Sreedharan SP, et al. (1997). Upregulation of neuropeptides and neuropeptide receptors in a murine model of immune inflammation in lung parenchyma. Am J Resp Cell Mol Biol 16:133–144.[Abstract]
Keany-Myers AM, Gause WC, Finkelman FD, Xhou X-D, Wills-Karp M (1998). Development of murine allergic asthma is dependent upon B7-2 costimulation. J Immunol160:1036–1043.
Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA, et al. (1995).B7.1 and B7.2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell80:707–718.[Medline]
Kulkarni-Narla A, Beitz AJ, Brown DR (1999). Catecholaminergic, cholinergic and peptidergic innervation of gut-associated lymphoid tissue in porcine jejunum and ileum. Cell Tissue Res 298:275–286.[Medline]
Lara-Marquez M, O'Dorisio M, O'Dorisio T, Shah M, Karacay B (2001). Selective gene expression and activation-dependent regulation of vasoactive intestinal peptide receptor type 1 and type 2 in human T cells. J Immunol166:2522–2530.
Larche M, Till SJ, Haselden BM, North J, Barkans J, Corrigan CJ, et al. (1998). Costimulation through CD86 is involved in airway antigen-presenting cell and T cell responses to allergen in atopic asthmatics. J Immunol 161:6375–6382.
Laskin DL, Pendino KJ (1995). Macrophages and inflammatory mediators in tissue injury. Ann Rev Pharmacol Toxicol 35:655–677.[Medline]
Lenardo MJ, Chan KM, Hornung F, McFarland H, Siegel R, Wang J, et al. (1999). Mature T lymphocyte apoptosis: immune regulation in a dynamic and unpredictable antigenic environment. Annu Rev Immunol 17:221–153.[Medline]
Lenschow DJ, Walunas TL, Bluestone JA (1996). CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258.[Medline]
Lolait SJ, Clemens JA, Markwick AJ, Cheng C, McNally M, Smith AI, et al. (1986). Pro-opiomelanocortin messenger ribonucleic acid and posttranslational processing of beta endorphin in spleen macrophages. J Clin Invest 77:1776–1779.
Martinez C, Delgado M, Pozo D, Leceta J, Calvo JR, Ganea D, et al. (1998). Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide modulate endotoxin-induced IL-6 production by murine peritoneal macrophages. J Leukocyte Biol 63:591–601.[Abstract]
Metwali A, Blum AM, Li J, Elliott DE, Weinstock JV (2000). IL-4 regulates VIP receptor subtype 2 mRNA (VPAC2) expression in T cells in murine schistosomiasis. FASEB J 14:948–954.
Miyata A, Arimura A, Dahl RR, Minamino N, Uehara A, Jiang L, et al. (1989). Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells. Biochem Biophys Res Commun164:567–574.[Medline]
Moore TC, Spruck CH, Said SI (1988). In vivo depression of lymphocyte traffic in sheep by VIP and HIV (AIDS)-related peptides. Immunopharmacology 16:181–189.[Medline]
Mosmann BL, White MV, Hohman RJ, Goldrich MS, Kaulbach HC, Kaliner MA (1993). Substance P, calcitonin gene-related peptide, and vasoactive intestinal peptide increase in nasal secretions after allergen challenge in atopic patients. J Allergy Clin Immunol 92:95–104.[Medline]
Muchamuel T, Menon S, Pisacane P, Howard MC, Cockayne DA (1997). IL-13 protects mice from LPS-induced lethal endotoxemia. J Immunol 158:2898–2903.[Abstract]
Nieber K, Baumgarten CR, Rathsack R, Furkert J, Oehme P, Kunkel G (1992). Substance P and beta-endorphin-like immunoreactivity in lavage fluid of subjects with and without allergic asthma. J Allergy Clin Immunol 90:646–654.[Medline]
Nohr D, Weihe E (1991). The neuroimmune link in the bronchus-associated lymphoid tissue (BALT) of cat and rat: peptides and neural markers. Brain Behav Immun 5:84–101.[Medline]
O'Garra AO (1998). Cytokines induce the development of functionally heterogenous T helper cell subsets. Immunity 8:275–283.[Medline]
Pankhaniya R, Jabrane-Ferrat N, Gaufo GO, Sreedharan SP, Dazin P, Kaye J, et al. (1998). Vasoactive intestinal peptide enhancement of antigen-induced differentiation of a cultured line of mouse thymocytes. FASEB J 12:119–127.
Pearse AGE, Polak JM, Bloom SR (1977). The newer gut hormone. Cellular sources, physiology, pathology, and clinical aspects. Gastroenterology 72:746–761.[Medline]
Pozo D, Delgado M, Martinez M, Guerrero JM, Leceta J, Gomariz RP, et al. (2000). Immunobiology of vasoactive intestinal peptide (VIP). Immunol Today 21:7–11.[Medline]
Przewlocki R, Hassan AH, Lason W, Epplen C, Herz A, Stein C (1992). Gene expression and localization of opioid peptides in immune cells of inflamed tissue: functional role in antinociception, Neuroscience 48:491–500.[Medline]
Rajora N, Ceriani G, Catania A, Star RA, Murphy MT, Lipton JM (1996). Alpha-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line. J Leukocyte Biol 59:248–253.[Abstract]
Rawlings SR, Hezareh M (1996). Pituitary adenylate cyclase activating polypeptide and PACAP/vasoactive intestinal polypeptide receptors: actions on the anterior pituitary gland. Endocrine Rev 17:4–29.[Medline]
Reglodi D, Somogyvari-Vigh A, Vigh S, Maderdrut JL, Arimura A (2000). Neuroprotective effects of PACAP38 in a rat model of transient focal ischemia under various experimental conditions. Ann NY Acad Sci 921:119–128.[Medline]
Ryu S, Jeong K, Yoon W, Park S, Kang B, Kim S, et al. (2000). Somatostatin and substance P-induced in vivo by lipopolysaccharide and in peritoneal macrophages stimulated with lipopolysaccharide or interferon-gamma have differential effects on murine cytokine production, Neuroimmunomodulation 8:25–30.[Medline]
Said SI, Mutt V (1969). A peptide fraction from lung tissue with prolonged peripheral vasodilator activity. Scand J Clin Lab Invest Suppl 107:51–56.[Medline]
Sallusto F, Lanzavecchia A, Mackay CR (1998). Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses. Immunol Today 19:568–574.[Medline]
Schratzberger P, Geiseler A, Dunzendorfer S, Reinisch N, Kahler CM, Wiedermann CJ (1998). Similar involvement of VIP receptor type I and type II in lymphocyte chemotaxis. J Neuroimmunol 87:73–81.[Medline]
Schwarz H, Villiger PM, von Kempis J, Lotz M (1994). Neuropeptide Y is an inducible gene in the human immune system. J Neuroimmunol 51:53–61.[Medline]
Singaram C, Sengupta A, Stevens C, Spechler SJ, Goyal RK (1991). Localization of calcitonin gene-related peptide in human esophageal Langerhans cells. Gastroenterology 100:560–563.[Medline]
Sherwood NM, Kruecki SL, McRory JE (2000). The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 21:619–670.
Smyth MJ (1997). Fas ligand-mediated bystander lysis of syngeneic cells in response to an allogeneic stimulus. J Immunol 158:5765–5772.[Abstract]
Sozzani S, Allavena P, Vecchi A, Mantovani A (2000). Chemokines and dendritic cell traffic. J Clin Immunol 20:151–160.[Medline]
Stalder T, Hahn S, Erb P (1994). Fas antigen is the major target molecule for CD4+ T cell-mediated cytotoxicity. J Immunol 152:1127–1133.[Abstract]
Streilein JW, Okamoto S, Sano Y, Taylor AW (2000). Neural control of ocular immune privilege. Ann NY Acad Sci 917:297–306.[Medline]
Suda T, Okazaki T, Naito Y, Yokota T, Arai N, Ozaki S, et al. (1995). Expression of the Fas ligand in cells of the T cell lineage. J Immunol 154:3806–3813.[Abstract]
Takahashi M, Ishimaru N, Yanagi K, Saegusa K, Haneji N, Shiota H, et al. (1999). Requirement for splenic CD4+ T cells in the immune privilege of the anterior chamber of the eye. Clin Exp Immunol 116:231–237.[Medline]
Thilenius ARB, Sabelko-Downes KA, Russell JH (1999). The role of the antigen-presenting cell in Fas-mediated direct and bystander killing: potential in vivo function of Fas in experimental allergic encephalomyelitis. J Immunol 162:643–650.
Trepicchio W, Bozza M, Pedneault G, Dorner A (1996). Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. J Immunol 157:3627–3634.[Abstract]
Tsunawaki S, Sporn M, Ding A, Nathan CF (1988). Deactivation of macrophages by transforming growth factor ß. Nature 334:260–262.[Medline]
Uchida D, Arimura A, Somogyvari-Vigh A, Shioda S, Banks WA (1966). Prevention of ischemia-induced death of hippocampal neurons by PACAP. Brain Res 736:280–286.
Van Snick J (1990). Interleukin 6: an overview. Annu Rev Immunol8:253–278.[Medline]
Varadhachary AS, Perdow SN, Hu C, Ramanarayanan M, Salgame P (1997). Differential ability of T cell subsets to undergo activation-induced cell death. Proc Natl Acad Sci USA 94:5778–5783.
Vassalli P (1992). The pathophysiology of the tumour necrosis factor. Annu Rev Immunol 10:411–452.[Medline]
Voice JK, Dorsam G, Lee H, Kong Y, Goetzl EJ (2001). Allergic diathesis in transgenic mice with constitutive T cell expression of inducible vasoactive intestinal peptide receptor. FASEB J 15:2489–2496.
Vollmar AM, Colbatzky F, Schulz R (1992). Expression of atrial natriuretic peptide in thymic macrophages after dexamethasone-treatment of rats. Cell Tissue Res 268:397–399.[Medline]
Wang R, Rogers AM, Ratliff RL, Russell JH (1996). CD95-dependent bystander lysis caused by CD4+ T helper 1 effectors. J Immunol157:2961–2968.[Abstract]
Weihe E, Nohr D, Michel S, Muller S, Zentel H-J, Fink T, et al. (1991). Molecular anatomy of the neuro-immune connection. Intern J Neurosci 59:1–23.[Medline]
Weinstock JV, Blum AM, Malloy T (1990). Macrophages within the granulomas of murine Schistosoma mansoni are a source of a somatostatin 1-14-like molecule. Cell Immunol131:381–390.[Medline]
Xia M, Sreedharan SP, Goetzl EJ (1996). Predominant expression of type II vasoactive intestinal peptide receptors by human T lymphoblastoma cells. J Clin Immunol 16:21–30.[Medline]
Xin Z, Sriram S (1998). Vasoactive intestinal peptide inhibits IL-12 and nitric oxide production in murine macrophages. J Neuroimmunol 89:206–212.[Medline]
Xin Z, Jiang X, Wang H-Y, Denny TN, Dittel BN, Ganea D (1997). Effect of vasoactive intestinal peptide (VIP) on cytokine production and expression of VIP receptors in thymocyte subsets. Regul Peptides 72:41–54.[Medline]
Yang X-J, Ogyzko VV, Nishikawa J, Howard BH, Nakatani Y (1996). A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature382:319–324.[Medline]
Zhang X, Brunner T, Carter L, Dutton RW, Rogers P, Bradley L, et al. (1997). Unequal death in T helper cell (Th)1 and Th2 effectors: Th1, but not Th2, effectors undergo rapid Fas/FasL-mediated apoptosis. J Exp Med 185:1837–1849.
