Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) act as potent anti-inflammatory agents that inhibit the... more
Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) act as potent anti-inflammatory agents that inhibit the function of activated macrophages and TH cells. Previous reports showed that VIP/PACAP inhibit IL-6 and TNF-alpha production in LPS-stimulated macrophages. The present study reports on the effect of VIP/PACAP on IL-10 production. Although VIP/PACAP do not induce IL-10 by themselves, they enhance IL-10 production in LPS-stimulated macrophages. The specific VPAC1 receptor mediates the stimulatory effect of VIP/PACAP, and cAMP is the major second messenger involved. VIP/PACAP increase IL-10 mRNA in LPS-stimulated cells, and the effect of transcriptional and protein synthesis inhibitors indicates de novo IL-10 production. Electromobility shift assays show that VIP/PACAP induce an increase in nuclear cAMP response element (CRE)-binding complexes, with CR...
Research Interests: Immunology, Neurochemistry, Immunology of the Gut, Biological Chemistry, Modulation, and 15 moreNeuroimmunology, Biological Sciences, Lipopolysaccharide, Glutamate, Neuropeptides, Nitric oxide, Blood, Clinical Sciences, CHEMICAL SCIENCES, Vasoactive Intestinal Peptide, FASEB J, Signaling pathway, Medical and Health Sciences, Cardiovascular medicine and haematology, and Paediatrics and reproductive medicine
We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammatory response and recovery of function following spinal cord injury (SCI). Female C57Bl/6 mice were exposed to spinal cord contusion injury... more
We evaluated the effects of the non-psychoactive cannabinoid cannabidiol (CBD) on the inflammatory response and recovery of function following spinal cord injury (SCI). Female C57Bl/6 mice were exposed to spinal cord contusion injury (T9-10) and received vehicle or CBD (1.5 mg/kg IP) injections for 10 weeks following injury. The effect of SCI and CBD treatment on inflammation was assessed via microarray, qRT-PCR and flow cytometry. Locomotor and bladder function and changes in thermal and mechanical hind paw sensitivity were also evaluated. There was a significant decrease in pro-inflammatory cytokines and chemokines associated with T-cell differentiation and invasion in the SCI-CBD group as well as a decrease in T cell invasion into the injured cord. A higher percentage of SCI mice in the vehicle-treated group (SCI-VEH) went on to develop moderate to severe (0-65.9% baseline thermal threshold) thermal sensitivity as compared with CBD-treated (SCI-CBD) mice. CBD did not affect recov...
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The UBASH3/STS/TULA family consists of two members sharing substantial homology and a similar multi-domain architecture, which includes a C-terminal histidine phosphatase domain capable of dephosphorylating phosphotyrosine-containing... more
The UBASH3/STS/TULA family consists of two members sharing substantial homology and a similar multi-domain architecture, which includes a C-terminal histidine phosphatase domain capable of dephosphorylating phosphotyrosine-containing substrates. TULA-family proteins act as downregulators of receptor-induced activation in several cell types, including T cells and platelets. Deletion of both family members in mice has been shown to result in hyperresponsiveness of T cells to T-cell receptor (TCR)/CD3 complex engagement, but little is known about the biological consequences of double knockout (dKO) and especially of either single KO (sKO). We elucidated the biological consequences of the lack of TULA-family proteins in dKO and TULA and TULA-2 sKO animals. In order to do so, we examined immune responses in Trinitrobenzene sulfonic acid (TNBS)-induced colitis, a mouse model of human inflammatory bowel disease, which is characterized by the involvement of multiple cell types, of which T cells have a crucial role, in the development of a pathological inflammatory condition. Our data indicate that TNBS treatment upregulates T-cell responses in all KO mice studied to a significantly higher degree than in wild-type mice. Although the lack of either TULA-family member exacerbates inflammation and T-cell responses in a specific fashion, the lack of both TULA and TULA-2 in dKO exerts a higher effect than the lack of a single family member in TULA and TULA-2 sKO. Analysis of T-cell responses and TCR-mediated signaling argues that the proteins investigated affect T-cell signaling by regulating phosphorylation of Zap-70, a key protein tyrosine kinase.
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Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is... more
Interleukin-23, a recently described cytokine produced by activated antigen-presenting cells, including dendritic cells, is a p19/p40 heterodimer. The p40 subunit is shared with IL-12, the major Th1-driving cytokine, while p19 is distantly related to IL-12 p35. IL-23 has pro-inflammatory actions, inducing IL-17 secretion from activated CD4+ T cells, and stimulating the proliferation of memory CD4+ T cells. Here, we examined the effects of PGE2, a well-known immunomodulator, on the production of IL-23 by bone marrow- derived dendritic cells (BM-DCs). Our results indicate that PGE2 increases the production of functional IL-23 from immature BM-DCs in a time- and dose-dependent manner. PGE2 induces both the expression of p19 and p40, without affecting p35 expression. The effect of PGE2 is mediated through the specific receptors EP2/4 and is mimicked by cAMP-inducing agents, such as forskolin and dbcAMP. Although PGE2 also induces IL-1beta and IL-6 expression in non-stimulated DCs, the stimulatory effect of PGE2 on IL-23 production is not mediated through IL-1beta or IL-6. GM-CSF, the pro-inflammatory cytokine required for the generation of BM-DCs, amplifies the IL-23 inducing activity of PGE2 in a synergistic manner. Recent studies described both pro- and anti-inflammatory effects of PGE2, and our results suggest an additional mechanism for its pro-inflammatory role, particularly significant for autoimmune diseases, such as rheumatoid arthritis.
Research Interests: Physiology, Biology, Inflammation, Medicine, Dendritic Cells, and 15 moreMice, cyclic AMP, Animals, Male, Dendritic cell, Medical Physiology, Arthritis, MISOPROSTOL, Lipopolysaccharides, Interleukins, Bone Marrow Cells, Biochemistry and cell biology, Gene Expression Regulation, Interleukin, and Bucladesine
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Research Interests: Immunology, Flow Cytometry, Dendritic Cells, Cellular Immunology, Lipopolysaccharide, and 13 moreMice, Animals, Male, Dendritic cell, TNF, Lipopolysaccharides, Tumor necrosis factor-alpha, Enzyme Linked Immunosorbent Assay, Glucocorticoids, Prostaglandin E2, Bone Marrow Cells, Inflammatory response, and reverse transcriptase polymerase chain reaction
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Research Interests: Immunology, Flow Cytometry, Immunology of the Gut, Confocal Microscopy, Apoptosis, and 12 moreTransgenic Mice, Mice, Animals, Cell Death, Vasoactive Intestinal Peptide, Protein Kinase, Enzyme Linked Immunosorbent Assay, Perforin, Gene Expression Regulation, Down-Regulation, Fas Ligand, and reverse transcriptase polymerase chain reaction
Abstract: Dendritic cells bridge innate and adap-tive immunity and participate in both responses. Upon capture of pathogens, dendritic cells release inflammatory cytokines and chemokines, attract-ing other immune cells to the infection... more
Abstract: Dendritic cells bridge innate and adap-tive immunity and participate in both responses. Upon capture of pathogens, dendritic cells release inflammatory cytokines and chemokines, attract-ing other immune cells to the infection site. Anti-inflammatory cytokines, glucocorticoids, anti-in-flammatory neuropeptides, and lipid mediators such as prostaglandin E2 (PGE2) limit and control the inflammatory response. In this study we report that exogenous PGE2 inhibits CCL3 (MIP-1) and CCL4 (MIP-1) expression and release from den-dritic cells stimulated with either lipopolysaccha-ride (LPS), a TLR4 ligand, or peptidoglycan, a TLR2 ligand. The inhibition is dose-dependent and occurs at both the mRNA and protein levels. The inhibitory effect is mediated through EP2 and EP4 receptors and requires the presence of PGE2 at the time of LPS stimulation. Intraperitoneal adminis-tration of PGE2 together with LPS results in a reduction in the levels of CCL3 and CCL4 released in the peritoneal fl...
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Research Interests: Immunology and Biology
High-output nitric oxide (NO) production from activated macrophages, resulting from the induction of inducible NO synthase (iNOS) expression, represents a major mechanism for macrophage cytotoxicity against pathogens. However, despite its... more
High-output nitric oxide (NO) production from activated macrophages, resulting from the induction of inducible NO synthase (iNOS) expression, represents a major mechanism for macrophage cytotoxicity against pathogens. However, despite its beneficial role in host defense, sustained high-output NO production was also implicated in a variety of acute inflammatory diseases and autoimmune diseases. Therefore, the down-regulation of iNOS expression during an inflammatory process plays a significant physiological role. This study examines the role of two immunomodulatory neuropeptides, the vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), on NO production by LPS-, IFN-gamma-, and LPS/IFN-gamma-stimulated peritoneal macrophages and the Raw 264.7 cell line. Both VIP and PACAP inhibit NO production in a dose- and time-dependent manner by reducing iNOS expression at protein and mRNA level. VPAC1, the type 1 VIP receptor, which is constituti...
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Vasoactive intestinal peptide (VIP) and the structurally related neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), present in the microenvironment of lymphoid organs, modulate the function of inflammatory cells... more
Vasoactive intestinal peptide (VIP) and the structurally related neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), present in the microenvironment of lymphoid organs, modulate the function of inflammatory cells through specific receptors. VIP and PACAP inhibit the production of pro-inflammatory agents and stimulate the production of anti-inflammatory cytokines in activated macrophages. The effect is mediated through specific receptors and involves shedding of the CD14 lipopolysaccharide (LPS) receptor and the transcriptional regulation of cytokine genes through effects on de novo expression or nuclear translocation of NFkappaB, cAMP-element binding protein (CREB), c-Jun, and interferon regulatory factor 1 (IRF-1). The in vivo administration of VIP/PACAP results in a similar pattern of cytokine modulation which, presumably, mediates the protective effect of VIP/PACAP in a high-endotoxic murine model for septic shock. VIP/PACAP reduce the expression of the costi...
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Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two structurally related neuropeptides produced within the lymphoid microenvironment, modulate several immunologic functions. We have... more
Vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two structurally related neuropeptides produced within the lymphoid microenvironment, modulate several immunologic functions. We have recently demonstrated that VIP and PACAP enhance the macrophage costimulatory activity for naive CD4+ T cells exposed to allogeneic or anti-CD3 stimuli through the differential regulation of the B7 costimulatory molecules. In this study, we report on the role of VIP and PACAP on macrophage B7 expression and costimulatory function for Ag-primed CD4+ T cells, and on the macrophage-induced regulation of Th1/Th2 differentiation in vitro and in vivo. VIP and PACAP up-regulate the costimulatory activity of macrophages for Ag-primed CD4+ T cells. VIP-/PACAP-treated macrophages gain the ability to induce Th2-type cytokines such as IL-4 and IL-5 and reduce Th1-type cytokines such as IFN-gamma and IL-2. In vivo administration of VIP or PACAP in Ag-immunized m...
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The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) downregulate cytokine production. Because human septic shock involves excessive cytokine production, the effect of... more
The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) downregulate cytokine production. Because human septic shock involves excessive cytokine production, the effect of VIP/PACAP was investigated in a high endotoxemia murine model. Both peptides protect against endotoxin-induced lethality and prevent septic shock-associated histopathological alterations. VIP/PACAP reduce serum and peritoneal TNFa and IL-6, suggesting that the protective effect is exerted by inhibiting the production of endogenous TNFa/IL-6. Consistent with this mechanism, VIP does not protect against septic shock induced by exogenous TNFa. The immunomodulatory role of VIP in vivo is supported by the appearance of high levels of VIP in serum and peritoneal fluid following LPS administration. Thus, the neuropeptides VIP/PACAP protect from the lethal effect of high endotoxemia, presumably by down-regulating TNFa and IL-6 production, and may offer an alterna...
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Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) act as potent anti-inflammatory agents that inhibit the... more
Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, and the structurally related pituitary adenylate cyclase-activating polypeptide (PACAP) act as potent anti-inflammatory agents that inhibit the function of activated macrophages and TH cells. Previous reports showed that VIP/PACAP inhibit IL-6 and TNF-alpha production in LPS-stimulated macrophages. The present study reports on the effect of VIP/PACAP on IL-10 production. Although VIP/PACAP do not induce IL-10 by themselves, they enhance IL-10 production in LPS-stimulated macrophages. The specific VPAC1 receptor mediates the stimulatory effect of VIP/PACAP, and cAMP is the major second messenger involved. VIP/PACAP increase IL-10 mRNA in LPS-stimulated cells, and the effect of transcriptional and protein synthesis inhibitors indicates de novo IL-10 production. Electromobility shift assays show that VIP/PACAP induce an increase in nuclear cAMP response element (CRE)-binding complexes, with CR...
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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. The... more
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. The production and release of cytokines by activated phagocytes are important events in the pathogenesis of ischemia-reperfusion injury. There is abundant evidence that the proinflammatory cytokine TNF-a is an important mediator of shock and organ failure complicating Gram-negative sepsis. VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon. In this study we have investigated the effects of VIP and the structurally related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP38) on the production of TNF-a by endotoxin-activated murine peritoneal macrophages. Both neuropeptides rapidly and specifically inhibit the LPS-stimulated production of TNF-a, exerting their action through the binding to VPAC1 rec...
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IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27... more
IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2 We showed previously that PGE2 inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and bindi...
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ABSTRACT
Vasoactive intestinal peptide (VIP), a neuropeptide present in the peptidergic innervation of lymphoid organs and expressed in thymocytes and peripheral lymphocytes, modulates cytokine expression in T lymphocytes. VIP down-regulates the... more
Vasoactive intestinal peptide (VIP), a neuropeptide present in the peptidergic innervation of lymphoid organs and expressed in thymocytes and peripheral lymphocytes, modulates cytokine expression in T lymphocytes. VIP down-regulates the expression of IL-2 and IL-10 mRNA in T cells stimulated through the TCR-associated CD3 complex. In contrast, IL-4 production is inhibited at a post-transcriptional level. In this study, we investigate the molecular mechanisms involved in the inhibition of IL-4 production by VIP. At the protein level, the time courses for IL-2 and IL-4 inhibition by VIP are different, with IL-4 being affected approximately 24 h later than IL-2. Northern blots and competitive reverse-transcription PCR analysis confirm the post-transcriptional inhibition of IL-4 production in both murine spleen cells and thymocytes activated through the CD3 complex. VIP does not affect IL-4 secretion, and does not induce a rapid IL-4 reuptake. Exogenous rIL-2 completely reverses the inhibitory effect of VIP, suggesting that VIP inhibits IL-4 production indirectly as a consequence of IL-2 inhibition. Studies regarding the newly synthesized IL-4 protein show that although VIP and exogenous IL-2 do not affect the rate of IL-4 synthesis, VIP reduces significantly the stability of the newly synthesized IL-4 protein, and exogenous IL-2 can restore it to the levels observed in activated cells in the absence of VIP. These results explore the molecular mechanisms involved in the neuroendocrine regulation of cytokine production, and support the idea that neuropeptides released or produced in the local lymphoid microenvironment may participate in the intricate cytokine network controlling local immune responses.
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MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN-β, used clinically in RR-MS reduces lesion formation and rates of relapse. Although the molecular mechanisms are not... more
MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN-β, used clinically in RR-MS reduces lesion formation and rates of relapse. Although the molecular mechanisms are not entirely elucidated, myeloid cells appear to be a major target for the therapeutic effects of IFN-β. DCs have a critical role in experimental models of MS through their effect on encephalitogenic Th1/Th17 cell differentiation and expansion. Here we focused on the effects of IFN-β on DC expression of cytokines involved in the control of Th1/Th17 differentiation and expansion. Administration of IFN-β to mice immunized with MOG35-55 inhibited IL-12 and IL-23 expression in splenic DC and reduced in vivo differentiation of Th1/Th17 cells. IFN-β affected cytokine expression in TLR-stimulated DC in a similar manner in vitro, inhibiting IL-12 and IL-23 and stimulating IL-10 at both mRNA and protein levels, by signaling through IFNAR. We investigated the role...
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The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of... more
The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP), two immunomodulatory neuropeptides, act as anti-inflammatory factors for activated microglia, by inhibiting the production of proinflammatory factors. In the present study the effects of VIP/PACAP on the MEKK1/MEK4/JNK transduction pathway and on the subsequent changes in Jun family members, a transduction pathway clearly involved in the activation of microglia cells were examined. VIP/PACAP inhibit MEKK1 activity and the subsequent phosphorylations of MEK4, JNK, and c-Jun, which result in a decrease in the AP-1 binding and a marked change in the composition of AP-1 complexes from c-Jun/c-Fos to JunB/c-Fos. Furthermore, VIP stimulates JunB production in LPS-stimulated microglia. Both inhibition of the MEKK1/MEK4/JNK pathway, leading to a reduction in phosphorylated c-Jun, and the stimulation of JunB are mediated through the specific VPAC1 receptor and cAMP/PKA pathway. The VIP...
Research Interests: Immunology, Immune response, Biological Chemistry, Biological Sciences, Cell line, and 15 moreNeuropeptides, Blood, Cell Death, Medical Physiology, Clinical Sciences, CHEMICAL SCIENCES, Glia, Anti Inflammatory Activity, Neurosciences, Cellular Molecular Biology, Biochemistry and cell biology, Fas Ligand, Medical and Health Sciences, Cardiovascular medicine and haematology, and Medical biochemistry and metabolomics
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We have constructed expression clones for mature rat interleukin-1 beta (IL-1 beta). Using these clones, rat recombinant IL-1 beta (rrIL-1 beta) was prepared and purified by a single-step cation-exchange chromatography method. In... more
We have constructed expression clones for mature rat interleukin-1 beta (IL-1 beta). Using these clones, rat recombinant IL-1 beta (rrIL-1 beta) was prepared and purified by a single-step cation-exchange chromatography method. In addition, synthetic rrIL-1 beta mRNA was transcribed and used to synthesize radiolabeled 35S-rrIL-1 beta for binding studies. The rrIL-1 beta produced was demonstrated to have IL-1 bioactivity in a mouse thymocyte proliferation assay, in which it could be blocked by inclusion of human recombinant IL-1 receptor antagonist (hrIL-1Ra). Similarly, rrIL-1 beta induced LIF mRNA expression in cultured rat sympathetic ganglia. In each case, the maximal dose of rrIL-1 beta was similar to that of human IL-1 beta. However, the peak response in rat tissue was twofold higher with rat IL-1 beta than with human IL-1 beta. The expression of rrIL-1 beta provides a useful tool for studying IL-1 receptors in rat, in which human and mouse IL-1 beta have been found to bind poorly. Species-specific activity of rat IL-1 beta may correlate with compensatory ionic properties of rat IL-1 receptor.
Research Interests: Cell Division, Biological Sciences, Humans, Mice, Animals, and 13 moreInterferon, Rats, Specific Activity, Species Specificity, Amino Acid Sequence, Base Sequence, Recombinant Proteins, Biological Assay, Leukemia Inhibitory Factor, Interleukin, Molecular Sequence Data, Thymus Gland, and Medical and Health Sciences
The neuropeptide VIP is present in high concentrations in normal lung, where it acts as a potent bronchodilator. VIP also downregulates T lymphocyte proliferation, possibly through its effect on cytokine expression. Although deficiencies... more
The neuropeptide VIP is present in high concentrations in normal lung, where it acts as a potent bronchodilator. VIP also downregulates T lymphocyte proliferation, possibly through its effect on cytokine expression. Although deficiencies in VIP levels are associated with asthma, VIP replacement therapy is impaired by its rapid degradation in the pulmonary microenvironment. A metabolically stable VIP peptide analog Ro 25-1553 has been developed and shown to act as a potent smooth muscle relaxant and suppressant of inflammatory cell accumulation. Proinflammatory cytokines play essential roles in inflammatory reactions. Here we compare the effects of VIP and Ro 25-1553 on IL-2, IL-4, and IFN-gamma production. Both VIP and Ro 25-1553 inhibit IL-2 and IL-4 but not IFN-gamma production and induce intracellular cAMP. Similar to VIP, Ro 25-1553 downregulates the IL-2 message and affects IL-4 production posttranscriptionally. Cytokines play important roles in allergic reactions, and increased cytokine levels are present in allergic asthmatic subjects. Therefore, downregulation of IL-2 and IL-4 production by Ro 25-1553 could play a significant role in the antiinflammatory activity of this peptide within the pulmonary microenvironment.