Biomedical subjects

D Ganea

Publications and source records attributed to D Ganea.

At least 55 records · Page 3Linked to original sources

PubMed1998

VIP and PACAP enhance IL-6 release and mRNA levels in resting peritoneal macrophages: in vitro and in vivo studies.

Vasoactive intestinal peptide (VIP), a neuropeptide produced by lymphocytes has been previously reported to modulate cytokine expression in T lymphocytes. In this study, we investigated the effects of VIP and of the structurally related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP38) on the production of IL-6 in unstimulated murine peritoneal macrophages. Both neuropeptides stimulate rapidly, specifically, and similarly the production of IL-6, exerting their action through two different receptor/signal transduction systems, i.e., primarily through the binding to VIP1/PACAP receptor followed by adenylate cyclase activation, and partially through the activation of protein kinase C following binding to PACAP-R. VIP and PACAP38 regulate the production of IL-6 at a transcriptional level, affecting the de novo synthesis of this cytokine. The stimulatory in vitro effect correlates with the stimulation of IL-6 expression and release in vivo. These studies suggest that VIP/PACAP play a role in immune system homeostasis, participating in the intricate cytokine network and controlling local immune responses. In addition, the understanding of the factors that regulate the expression and release of IL-6 by macrophages is important for the elucidation of the role of IL-6 in health and disease.

Animals↗

PubMed1998

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 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 microg/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.

Adenylyl Cyclases↗

PubMed1997

Effect of vasoactive intestinal peptide (VIP) on cytokine production and expression of VIP receptors in thymocyte subsets.

Intrathymic T cell precursors undergo a programmed sequence of developmental changes resulting in the production of mature, self-MHC restricted, single positive T lymphocytes which migrate to the periphery. The intrathymic T cell development is controlled by various factors, including cytokines and possibly neuroendocrine hormones. Our previous studies indicate that vasoactive intestinal peptide (VIP) inhibits IL-2 and IL-4 production in thymocytes through different molecular mechanisms. Thymocytes acquire the competence to express IL-2 and IL-2R during thymic development in a maturation-dependent manner. In this study we investigate the effect of VIP on IL-2 production, and the expression of VIP-R1 and VIP-R2 mRNA in different thymocyte subsets in comparison to T cell lines. All thymocyte subsets and T cell lines tested express VIP-R2. In contrast, only single positive, CD4+8- and CD4-8+ thymocytes express VIP-R1. VIP inhibits IL-2 production in CD4+8+ and single positive CD4+8- and CD4-8+ thymocytes and in TH1 cells stimulated through the TCR. No inhibition is observed in CD3-4-8- and single positive CD4+8- and CD4-8+ thymocytes, or in TH1 cells stimulated by a combination of calcium ionophores and phorbol esters. These findings suggest that VIP inhibits IL-2 production through VIP-R2, and that it interferes with a TCR-connected transduction pathway. We also investigate the expression of VIP mRNA in thymocyte subsets and T cell lines, and conclude that thymocytes as well as antigen-specific T cells may function as VIP sources within the lymphoid organs.

Animals↗

PubMed1997

Vasoactive intestinal peptide stimulates p59fyn kinase activity in murine thymocytes.

The neuropeptide VIP has immunomodulatory properties, including the inhibition of cytokine production (IL-2, IL-4, and IL-10) in T lymphocytes stimulated through their TCR. The transduction pathways involved in the inhibitory effect of VIP on IL-2 expression are not known. Here we investigate the effect of VIP on the T-cell-specific protein tyrosine kinases p56lck and p59fyn in resting and stimulated thymocytes. VIP does not affect lck or fyn activity in stimulated thymocytes and does not alter the general pattern of cellular tyrosine phosphorylation. However, VIP stimulates p59fyn, but not p56lck, kinase activity in resting thymocytes. The effect is dose dependent, exhibits a specific time course, and is reproduced by other cAMP-inducing agents such as forskolin, prostaglandin E2, and 8-bromo-cAMP, suggesting that cAMP may function as the intracellular mediator.

Animals↗

PubMed1996

Down-regulation of cytokine expression in murine lymphocytes by PACAP and VIP.

Neuropeptides, such as VIP and PACAP, released or produced in the microenvironment of the primary and secondary lymphoid organs, could affect a variety of immune responses through the regulation of cytokine expression. VIP has been previously shown to inhibit IL-2, IL-4, and IL-10 production in murine lymphocytes stimulated through the TCR-associated CD3 complex. This study shows that, similar to VIP, PACAP-38 inhibits IL-2 production in T lymphocytes. Comparisons with forskolin, a known cAMP inducer, suggest that the increase in intracellular cAMP represents at least one of the transduction pathways involved in IL-2 inhibition, especially in the higher range of neuropeptide concentration. Studies of the detailed molecular mechanisms involved in the regulation of IL-2 expression indicate that reduction of de novo transcription and destabilization of the message contribute to the reduction of steady-state IL-2 mRNA levels following VIP treatment. Examination of several IL-2 transcriptional factors indicates that only NFAT is down-regulated by VIP. Neuropeptides, such as VIP and PACAP, which specifically modulate the expression of various cytokines, could play an important role in the intricate cytokine network controlling local immune responses.

Animals↗

PubMed1996

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide-38 inhibit IL-10 production in murine T lymphocytes.

Vasoactive intestinal peptide (VIP), a neuropeptide present in the peptidergic innervation of lymphoid organs and expressed in thymocytes and peripheral lymphocytes has been previously reported to modulate cytokine expression in T lymphocytes. In this study, we investigated the effects of VIP and of the structurally related neuropeptide PACAP-38 on the expression of IL-10 in murine lymphocyte cultures. Both neuropeptides inhibit IL-10 production by spleen cells or thymocytes activated via the TCR-associated CD3 complex in a similar dose-response manner. The inhibition is specific, presumably mediated through the VIP-R1, and maximum inhibitory levels are achieved within the first 5 to 15 min of exposure to VIP or PACAP-38. CD4+ T cells function as direct cellular targets for the two neuropeptides. The fact that VIP, PACAP-38, and forskolin, all known cAMP inducers, also inhibit IL-10 production, suggests the participation of cAMP in signal transduction. VIP and PACAP-38 regulate transcriptional expression of IL-10, since IL-10 steady state mRNA levels are significantly reduced by treatment with the two neuropeptides. These results expand the range of neuroendocrine-regulated cytokines and support the idea that neuropeptides such as VIP and PACAP, which are released or produced in the local lymphoid microenvironment and specifically modulate the expression of various cytokines, may participate in the intricate cytokine network controlling local immune responses.

Animals↗

PubMed1996

Vasoactive intestinal peptide inhibits IL-4 production in murine T cells by a post-transcriptional mechanism.

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.

Animals↗

PubMed1996

Differential expression of vasoactive intestinal peptide receptors 1 and 2 (VIP-R1 and VIP-R2) mRNA in murine lymphocytes.

Vasoactive intestinal peptide (VIP), a neuropeptide present in the lymphoid microenvironment, modulates cytokine expression and affects T cell proliferation. Recent molecular studies identified two VIP receptors. VIP-R1 and VIP-R2, primarily in nonlymphoid cells. In this study, we investigate the expression of VIP-R1 and VIP-R2 mRNA in unstimulated and stimulated lymphocytes and thymocytes, and in various lymphocyte subpopulations. In contrast to VIP-R1 which is constitutively expressed, the expression of VIP-R2 is induced only following stimulation through the TCR-associated CD3 complex. Both CD4+ and CD8+ T cells express VIP-R1 and VIP-R2. Two T cell lines, EL-4.IL-2 and D10.G4.1 express exclusively VIP-R2. VIP induces the expression of the VIP-R2 gene in the absence of additional stimuli. Differential expression and regulation of the two VIP receptors in T lymphocytes suggests different physiological roles in mediating the immunomodulatory activities of VIP and related neuropeptides.

Animals↗

PubMed1996

Murine T-lymphocytes express vasoactive intestinal peptide receptor 1 (VIP-R1) mRNA.

Vasoactive intestinal peptide (VIP), a neuropeptide present in primary and secondary lymphoid organs has been previously reported to inhibit IL-2 and IL-4 production as well as the proliferation of mitogen- or antigen-stimulated T-cells. Binding studies suggested that the immunoregulatory effects of VIP are mediated through specific VIP-binding sites present on lymphocyte subpopulations. Here we report on the expression of VIP-R1 mRNA in various murine lymphocyte subpopulations. By using RT-PCR. RNase protection assay, cDNA cloning, and sequence analysis, we show that stimulated and unstimulated murine spleen cells, thymocytes. CD4+ and CD8+ T-cells express VIP-R1. The VIP-R1 fragment amplified from murine brain, thymocytes, spleen cells and CD4+ T-cells share identical nucleotide sequences, and a high degree of homology with the corresponding nonlymphoid rat and human VIP-R1 sequences. The expression of VIP-R1 in thymocytes and peripheral lymphocytes, and especially in the CD4+ T-cell subset supports the idea that VIP produced or released locally in the lymphoid microenvironment could directly affect cytokine production and proliferation of T-lymphocytes.

Animals↗

PubMed1996

Regulatory effects of vasoactive intestinal peptide on cytokine production in central and peripheral lymphoid organs.

Vasoactive intestinal peptide (VIP) belongs to an ever growing family of neuropeptides with immunomodulatory functions. VIP-containing nerve fibers are present in both primary and secondary lymphoid organs, frequently in close proximity to immune cells. In addition, several types of immune cells, including T lymphocytes may function as local VIP sources in the lymphoid microenvironment. VIP released from neuronal and/or non neuronal sources exerts immunomodulatory effects through direct binding to VIP receptors (VIP-Rs), which are expressed on most immune cells. The existence of lymphocytic VIP-Rs has been demonstrated initially through binding studies, and more recently, through molecular biology technology. Both VIP-R1 and VIP-R2, which express high affinity for VIP and related neuropeptides such as the pituitary adenylate cyclase activating peptide (PACAP), are present on lymphocyte subsets, and recent reports suggest that whereas VIP-R1 is expressed constitutively, VIP-R2 expression is induced upon lymphocyte activation. Although VIP affects a variety of immune functions, its primary immunomodulatory function seems to be anti-inflammatory in nature. Whereas a rapid inflammatory response is essential for the ultimate elimination of foreign antigens, its intensity and duration have to be strictly controlled to avoid extensive tissue damage. In this respect, neuropeptides with anti-inflammatory functions such as VIP or the structurally related PACAP, timely released within the lymphoid organs, could play an important physiological role in the down-regulation of the immune response. Cytokines, soluble products of immune cells, play major roles in lymphocyte development, activation, and differentiation. As most cytokines are functionally pleiotropic, redundant, and interdependent, local interactions within the cytokine-neuroendocrine network have significant impact on cytokine production and function. Therefore, the immunomodulatory activities of VIP could be mediated, at least partially, through effects on the production of cytokines. The purpose of this article is to review the existing information regarding the VIP modulation of cytokine expression in immune cells. Both VIP and PACAP downregulate the expression of IL-2 mRNA and protein in T cells activated through the T cell receptor, through reducing both the stability and the de novo transcriptional rate of the IL-2 message. Reduction in the amount of IL-2 generated by the activated CD4+ T cells impacts on both T cell proliferation and on further sequential cytokine production. This is indeed the case with IL-4, which is affected by VIP indirectly, through inhibition of IL-2. In contrast, the inhibitory effect of VIP and PACAP on IL-10 production proceeds through a direct transcriptional event. In contrast to IL-2 which functions solely as a proinflammatory cytokine, IL-4 and IL-10 act as pro- or anti-inflammatory cytokines, depending on their involvement in specific immune responses. Therefore, depending on interactions with the local cytokine network, VIP and related neuropeptides may contribute significantly to controlling the amplitude and timing of the inflammatory response to foreign antigens. Although the role of VIP and related peptides on T cell development has not been investigated yet, the presence of VIP and VIP-Rs in the thymus, and their effect on thymic cytokine production, suggests that VIP and/or PACAP released locally within the thymic environment could also affect T cell development, and therefore participate in the generation and maturation of immune cells.

Animals↗

PubMed1995

Species-specific activity of rat recombinant interleukin-1 beta.

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.

Amino Acid Sequence↗

PubMed1995

Neuropeptide regulation of cytokine expression: effects of VIP and Ro 25-1553.

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.

Animals↗

PubMed1994

Induction of IL-3 and granulocyte-macrophage colony-stimulating factor by substance P in bone marrow cells is partially mediated through the release of IL-1 and IL-6.

Experimental data strongly suggest that the nervous and immune systems are interrelated. One example of this interrelation is anatomical and is represented by innervation of the lymphoid organs by substance P (SP) immunoreactive fibers, among others. Neurotransmitters/neuropeptides can exert functional receptor-mediated immunologic responses. SP binding to its receptor induces cytokine production in macrophages and T cells and stimulates IgG secretion from B cells. SP has also been associated with inflammation and other immune-mediated diseases such as arthritis. We have previously reported an in vitro stimulatory effect of SP on hematopoiesis that was mediated mostly by the induction of two relevant hematopoietic growth factors, IL-3 and granulocyte-macrophage-CSF (GM-CSF). In this study, we have shown that SP, through the carboxyl terminus, induces the production of IL-3 and GM-CSF in bone marrow mononuclear cells. This production requires de novo synthesis and is blocked by two different SP-R antagonists, spantide and CP-96,345-1. The induction of IL-3 and GM-CSF is partially mediated by IL-1 and IL-6, which are also produced by bone marrow mononuclear cells. Furthermore, the production of IL-3 and GM-CSF correlated with an accumulation of their respective steady state mRNAs. T cells found within the bone marrow are responsible for most of the induced IL-3. Because SP mediates the release of IL-1, IL-3, IL-6, and GM-CSF, all important hematopoietic regulators, by bone marrow cells, this study further suggests the possibility of a regulatory role of the nervous system in hematopoiesis mediated by neuropeptides such as SP.

Animals↗

PubMed1994

Vasoactive intestinal peptide inhibits interleukin (IL)-2 and IL-4 production in murine thymocytes activated via the TCR/CD3 complex.

During their development in the thymus, T cells acquire interleukin (IL)-2 and IL-4 inducibility in a developmentally controlled manner. Although the role of IL-2 and IL-4 in T cell development is still unclear, several reports indicated that IL-2/IL-2R and IL-4/IL-4R interactions in the thymus could play an important role in T cell development. The presence of vasoactive intestinal peptide (VIP)-immunoreactive cells and nerve fibers in the thymus suggests the possible local release of the neuropeptide in the thymic microenvironment. VIP has been previously reported to inhibit IL-2 and IL-4 production, as well as the proliferation of mitogen- or antigen-stimulated peripheral T cells. Here we report on the effect of VIP on IL-2 and IL-4 production by and proliferation of murine thymocytes stimulated through the TCR/CD3 receptor. VIP inhibited both IL-2 and IL-4 production, as well as the proliferation of murine thymocytes in a dose-dependent and specific manner. Structurally related peptides such as secretin or glucagon had little or no inhibitory activity. The intact VIP molecule was required for the inhibitory effect, since amino- or carboxy-terminal fragments did not inhibit IL-2 production. The inhibitory effect of VIP was observed for VIP additions up to 12 h after the initiation of the cultures, and incubations longer than 3 h were required for maximum inhibitory effects. Through its downregulatory effect on IL-2 and IL-4 production, locally released VIP could potentially affect T cell development within the thymus.

Animals↗

PubMed1994

Extrachromosomal eukaryotic DNA substrates for switch recombination: analysis of isotype and cell specificity.

Switch recombination in B lymphocytes is a complex process directed by signals provided by cytokines and/or TH cells. To analyze these signals in an in vitro system, we have developed extrachromosomal eukaryotic substrates for switch recombination that replicate autonomously in murine cells and present pairs of switch (S) regions in an accessible mode. Switch recombination within the S regions results in the expression of the selectable neo gene. The results presented here indicate that substrates containing either S mu and S gamma 2b, S mu and S gamma 2a, or S mu and S alpha undergo switch recombination with similar frequencies in the pre-B-cell line 18-81, which has been previously reported to specifically switch to IgG2b. This indicates that, rather than expressing a gamma 2b isotype-specific recombinase, the 18-81 cells express a switch recombinase capable of acting on any accessible S region, supporting the accessibility model. The extrachromosomal substrates were rearranged in the 18-81 cells, but not in murine myeloma, T-cell, or fibroblast cell lines, supporting the idea that switch recombination is indeed regulated in a cell- and developmentally specific manner. Restriction enzyme analysis of the plasmid DNA recovered from the selected cell lines suggested multiple recombinational events, with most patterns in agreement with deletions within one or both switch regions.

3T3 Cells↗

PubMed1993

Stimulation of IL-2 production in murine lymphocytes by substance P and related tachykinins.

Substance P (SP), a tachykinin neuropeptide, has been previously reported to stimulate IL-2 production in murine T cell lines activated with phorbol esters. Here we extend these observations by establishing the stimulatory effect of SP and related tachykinins on IL-2 production by normal murine lymphocytes and on purified CD4+ T cells. SP proved to be the most efficient IL-2 inducer, exerting its maximal effect at concentrations that were 4 to 5 orders of magnitude lower than the optimal stimulatory concentrations of physalaemin, NKA, or NKB. SP stimulated IL-2 production in a dose-dependent manner, with an optimal concentration range of 10(-10) to 10(-14) M, comparable with physiologic concentrations of SP found in blood and other organs. The effect of SP was carried by the carboxyl-terminal part of the molecule (SP4-11). The specificity of SP activity was confirmed by the inhibitory effect of spantide, a tachykinin antagonist, and of CP-96,345, a nonpeptide antagonist specific for NK-1-type receptors. In unfractionated spleen cell cultures SP induced de novo IL-2 protein synthesis. SP could induce IL-2 production either directly, or in combination with Con A or anti-CD3 antibody treatments. The effect of SP in conjunction with Con A was synergistic, whereas the effect in conjunction with anti-CD3 antibodies was additive, suggesting different molecular mechanisms for these stimulatory factors. In the absence of additional costimuli the effect of SP in unfractionated spleen cell cultures was partially mediated through the induction of IL-1, and both SP and IL-1 were required for IL-2 induction in purified CD4+ T cells. In contrast to its stimulatory effect on the generation of IL-2, SP did not induce IFN-gamma production in murine spleen cells. The stimulatory effect of SP on IL-2 production suggests that some of the already described immunostimulatory activities of SP could be mediated through the up-regulation of IL-2 production in normal lymphocytes.

Animals↗

PubMed1993

In vitro stimulatory effect of substance P on hematopoiesis.

The neuropeptide Substance P (SP) is widely distributed in the peripheral nervous system. Its biologic effects have been extensively studied in the immune system. However, even though the bone marrow (BM) is innervated with SP-immunoreactive fibers and some of its cells not only express SP receptors (T and B cells, endothelial cells, and macrophages) but also produce SP (macrophages, eosinophils, and endothelial cells), the effects of SP on hematopoiesis are scanty. Furthermore, SP induces the production of hematopoietic growth factors (HGFs) (interleukin-1 [IL-1], IL-6, and tumor necrosis factor alpha) from human monocytes. In this study, we have found a potent in vitro stimulatory effect of SP (10(-8) to 10(-12) mol/L) on hematopoiesis for both erythroid and granulocytic progenitors in short-term methyl-cellulose BM cultures. SP alone, in the absence of exogenous HGFs, is able to sustain hematopoiesis in vitro. This stimulatory effect of SP is: (1) mostly mediated by the adherent cells; (2) completely abrogated by two SP receptor (SP-R) antagonists; and (3) partially reduced by anti-IL-1, IL-3, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Furthermore, it appears that the stimulatory effect of SP may be mediated by IL-3 and GM-CSF because we have also found that SP induces the release of these two cytokines from BM mononuclear cells. Considering that the SP effect occurs at concentrations as low as 10(-11) mol/L, and via a specific receptor, it appears that SP may play a physiologic role in regulating hematopoiesis, at least partially through the adherent BM cells and the release of HGFs, and may place SP, a neuropeptide, in a new category of hematopoietic regulators.

Antibodies, Monoclonal↗

PubMed1993

Vasoactive intestinal peptide downregulates the expression of IL-2 but not of IFN gamma from stimulated murine T lymphocytes.

The neuropeptide vasoactive intestinal peptide (VIP) has been previously reported to inhibit T cell proliferation. Here we report on the effect of VIP on IL-2 and on IFN gamma production by murine T lymphocytes stimulated with mitogens (ConA), or activated through the antigen-specific T cell receptor. VIP inhibited IL-2 production by either unfractionated spleen cells, or by purified CD4+ T cells in a dose-dependent manner. The effect was specific, since structurally related peptides such as secretin and glucagon had little or no inhibitory effect. VIP induced a rapid increase in intracellular cAMP in CD4+ T cells, suggesting that the inhibitory effect of VIP could be mediated through the induction of cAMP. Northern blots showed that VIP downregulated IL-2 mRNA, indicating the occurrence of a transcriptional regulatory event. In contrast with its effect on IL-2, VIP did not affect IFN gamma production by either mitogen-stimulated normal T lymphocytes, or by the L12R4 murine T cell line which produces IFN gamma in response to PMA stimulation.

Animals↗