vasoactive-intestinal-peptide and Granuloma

Schistosomiasis is a parasitic disease in which focal inflammatory responses called granulomas develop in the liver and intestines. The inflammatory cells within these granulomas produce authentic vasoactive intestine peptide (VIP). VIP acts as an immune modulator. In the schistosome granuloma, VIP can suppress T cell proliferation and T lymphocyte IL-2 production. Also, it can enhance IL-5 production from granuloma T cells. The granuloma T cells bear authentic VIP receptors of both the VIPr1 and VIPr2 subclasses. It is probable that the expression of these receptors is subject to immunoregulation, which is the topic of current investigation. Moreover, differences in the structure of VIPr1 and VIPr2 suggest that each may have unique immunoregulatory functions in inflammation.

Topics: Animals; Granuloma; Inflammation; Mice; Schistosomiasis mansoni; Vasoactive Intestinal Peptide

In schistosomiasis, eggs induce granulomas that have a vasoactive intestinal peptide (VIP) immunoregulatory circuit. This study explored the regulation of VIP production at sites of inflammation. Splenocytes from uninfected C57BL/6 mice expressed VIP mRNA and protein, which stopped following egg deposition. Eggs induce a Th2 response, suggesting that Th2 cytokines like interleukin (IL)-4 can regulate VIP. To address this issue, splenocytes from uninfected mice were incubated for 4 h with or without recombinant IL-4. IL-4 inhibited VIP mRNA expression. F4/80+ macrophages were the source of constitutively expressed VIP, subject to IL-4 regulation. In IL-4 knockout mice, splenic VIP production did not downmodulate during schistosome infection, suggesting that IL-4 is a critical cytokine regulating VIP production in wild-type mouse spleen. IL-4-producing granulomas in schistosomiasis made VIP. Experiments showed that granuloma VIP derived from F4/80- (nonmacrophage) cell populations, explaining this paradox. Granuloma F4/80+ cells from IL-4 knockout mice expressed VIP. Thus macrophages can make VIP, which is subject to IL-4 regulation. However, in the Th2 granulomas, other cell types produce VIP, which compensates for loss of macrophages as a source of this molecule.

Topics: Animals; Cells, Cultured; Granuloma; Interleukin-4; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Precursors; Recombinant Proteins; Reference Values; RNA, Messenger; Schistosomiasis mansoni; Spleen; Vasoactive Intestinal Peptide

Mice infected with Schistosoma mansoni mount focal granulomatous responses around each ovum that deposits in the liver and intestinal wall. The granulomas ultimately destroy the ova while absorbing the released toxic, injurious agents. The granulomas contain T cells and other cell types, all of which are under control. For example, T lymphocyte proliferation in situ within the granulomas is probably restrained by various regulatory mechanisms. Granuloma eosinophils make VIP, and granuloma T cells have VIP receptors. Yet, the function of VIP within the granulomatous response is unknown. We studied the effect of VIP on granuloma and splenic T cell proliferation in response to Con A or soluble egg antigens (SEA). [3H]Thymidine incorporation was used to assess the rate of proliferation. VIP decreased Con A- or SEA-induced, T lymphocyte proliferation. Suppression of proliferation was most evident for T cells stimulated submaximally with mitogen or antigen. Since T lymphocyte proliferation in response to antigen or mitogen requires soluble lymphokines, we investigated the capacity of VIP to alter the expression of several lymphokines as a possible mechanism for mediating suppression of T cell proliferation. VIP decreased IL-2 production, but did not effect IL-5 or IFN-gamma release. The effect of VIP on IL-2 production was dependent on the presence of a CD4+ T lymphocyte subset. VIP could no longer modulate lymphocyte proliferation if exogenous rIL-2 was added to the cultures. The addition of neutralizing anti-IL-2 mAb, but not anti-IL-4 mAb, substantially decreased granuloma lymphocyte proliferation in response to antigen or mitogen. This suggested that granuloma T cell proliferation required endogenously produced IL-2. These findings suggest that VIP may help modulate granuloma T cell proliferation through regulation of IL-2 production.

Topics: Animals; CD4-Positive T-Lymphocytes; Concanavalin A; Enterotoxins; Female; Granuloma; Interleukin-2; Lymphocyte Activation; Mice; Mice, Inbred CBA; Recombinant Proteins; Schistosoma mansoni; Schistosomiasis mansoni; Spleen; T-Lymphocytes; Vasoactive Intestinal Peptide

In murine schistosomiasis, granulomas form around ova deposited in the liver and intestines of infected mice. The granulomas have eosinophils that produce vasoactive intestinal peptide (VIP) and T cells that display VIP receptors. IL-5 is a lymphokine important for the development and maturation of eosinophils. It seemed plausible that VIP, released from eosinophils, may interact with lymphocyte VIP receptors and modulate IL-5 production as part of a feedback regulatory circuit. Thus, we determined whether granuloma T cells make IL-5 and whether VIP modulates IL-5 production. Isolated granuloma cells enriched for T lymphocytes spontaneously released IL-5. Culture of these cells in the presence of VIP increased IL-5 secretion. Spleen cells were also studied. Spleen cells from infected mice did not spontaneously release IL-5 or express IL-5 mRNA and VIP did not stimulate these resting spleen cells to produce this IL. However, these cells did express IL-5 mRNA and secreted IL-5 in response to Con A or soluble egg Ag. VIP could not appreciably modulate IL-5 release when cells were cultured with VIP and the Ag or mitogen. Spleen cells washed free of Con A ceased IL-5 secretion within 24 h. These preactivated splenic T cells resumed vigorous IL-5 secretion in response to either Con A or VIP. Yet only Con A prominently induced IL-5 mRNA expression. VIP was an effective stimulus at concentrations equal to or above the kDa of the VIP receptor on both splenic and granuloma T cells (10(-8) M). It is concluded that, in murine schistosomiasis, VIP invokes IL-5 release from activated T cells that are not undergoing immediate TCR stimulation.

Topics: Animals; Antigens, Helminth; Concanavalin A; Eosinophils; Female; Gene Expression; Granuloma; Interleukin-5; Lymphocyte Activation; Mice; Mice, Inbred CBA; RNA, Messenger; Schistosomiasis mansoni; Spleen; T-Lymphocytes; Vasoactive Intestinal Peptide

Granulomas develop around schistosome ova in murine Schistosoma mansoni. These granulomas have eosinophils that produce VIP. It is possible that VIP participates in immunoregulation. VIP-mediated effects usually operate through a cAMP-dependent mechanism. To identify VIP-responsive inflammatory cells in murine schistosomiasis, inflammatory cells were exposed to VIP and assessed for adenylate cyclase activation and VIP binding. VIP increased adenylate cyclase activity in splenic lymphocytes from both normal and infected mice. In each case, the half-maximal stimulation was at about 5 x 10(-8) M. [125I]VIP bound to splenic lymphocytes specifically, with a Kd of 10(-8) M. This suggested that maximal adenylate cyclase activation requires full receptor occupancy. The receptor was highly specific for VIP. Hormone analogs, that are VIP receptor antagonists in some tissues, were only weak agonists of the lymphocyte VIP receptor. Granuloma cells also bound VIP and responded with adenylate cyclase activation in a manner similar to that of spleen cells. Both splenic T and B lymphocytes responded to VIP. Deletion experiments, using anti-Thy 1.2, suggested that most of the responsive granuloma cells were T lymphocytes. Thus, VIP alters cAMP metabolism in granuloma T cells through a receptor-coupled mechanism similar to that observed for spleen cells. Binding studies on mouse intestinal epithelial cells suggested that their VIP receptor is functionally and possibly structurally different from the VIP receptor on mouse lymphocytes. Additional experiments suggested that VIP and other neuropeptides are unlikely to alter the granulomatous response through a primary interaction with the granuloma macrophages.

Topics: Adenylyl Cyclases; Animals; Enzyme Activation; Female; Granuloma; Macrophages; Mice; Mice, Inbred CBA; Phagocytosis; Receptors, Gastrointestinal Hormone; Receptors, Vasoactive Intestinal Peptide; Schistosomiasis mansoni; Somatostatin; Spleen; T-Lymphocytes; Vasoactive Intestinal Peptide

Schistosomiasis mansoni is a parasitic disease in which granulomas form around schistosome eggs in the liver and intestines. The purpose of this study was to determine the alterations in the intrinsic innervation of the distal ileum and proximal colon resulting from schistosomiasis. Using murine schistosomiasis mansoni, we examined light microscopic preparations stained with osmium-zinc iodide or the dihydronicotinamide adenine dinucleotide: nitro BT oxidoreductase (NADH) method. We also examined specific populations of peptidergic nerves (vasoactive intestinal polypeptide and substance P) using an avidin-biotin complex (ABC) immunohistochemical technique. We found that granulomas focally destroyed the enteric nerves. Occasionally nerves were found within granulomas, particularly at the periphery of the lesions. Nerve cell bodies close to granulomas had altered staining, which included increased staining for vasoactive intestinal polypeptide. The distribution of nerve injury varied between the 2 enteric segments studied. In the distal ileum, the principal injury was to the myenteric plexus; whereas, the submucous and mucosal plexuses were predominantly damaged in the proximal colon. The physiologic significance of this injury to the enteric nerves requires elucidation.

Topics: Animals; Colon; Female; Granuloma; Ileum; Immunohistochemistry; Mice; Mice, Inbred CBA; Schistosomiasis mansoni; Substance P; Vasoactive Intestinal Peptide

Schistosomiasis mansoni is a parasitic disease resulting in the deposition of ova predominantly in the liver and intestines. These ova secrete antigens which induce host sensitization and evoke focal granulomas. The granulomas are intricate delayed-hypersensitivity reactions governed by numerous cellular and humoral interactions. They displace or destroy normal tissue. Vasoactive intestinal peptide (VIP) is one of several neuropeptides which exert a broad range of biologic actions that may include modulation of immune responses. In this study, VIP was sought within liver granulomas isolated from Schistosoma mansoni-infected, CBA/J mice. Granuloma extracts contained appreciable amounts of immunoreactive VIP as detected by radioimmunoassay. Immunoreactive VIP was shown, by each of two chromatographic methods, to elute as a single peak coinciding with that of synthetic VIP. In situ hybridization was performed with an oligonucleotide probe complementary to a portion of the nucleotide sequence encoding VIP on preproVIP mRNA (antisense probe). Radiolabeled VIP probe adhered exclusively to granuloma eosinophils and to eosinophils within a peritonitis induced in normal mice by proteose peptone. Hybridization of radiolabeled VIP probe in the presence of unlabeled probe substantially attenuated binding. A sense probe failed to bind. These data suggest that the granulomas contain authentic VIP and that eosinophils express the gene for this molecule.

Topics: Animals; Female; Gene Expression; Granuloma; Mice; Mice, Inbred CBA; Nucleic Acid Hybridization; RNA, Messenger; Schistosomiasis; Vasoactive Intestinal Peptide