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J Leceta

Publications and source records attributed to J Leceta.

At least 19 recordsLinked to original sources
PubMed2001

Vasoactive intestinal peptide in the immune system: potential therapeutic role in inflammatory and autoimmune diseases.

Vasoactive intestinal peptide (VIP), a neuropeptide that is produced by lymphoid as well as neural cells, exerts a wide spectrum of immunological functions, controlling the homeostasis of the immune system through different receptors expressed in various immunocompetent cells. In the last decade, VIP has been clearly identified as a potent anti-inflammatory factor, which acts by regulating the production of both anti- and pro-inflammatory mediators. In this sense, VIP has been described to prevent death by septic shock, an acute inflammatory disease with a high mortality. In addition, VIP regulates the expression of co-stimulatory molecules, this being an action that may be related to modulating the shift toward Th1 and Th2 differentiation. We have recently reported that VIP prevents the deleterious effects of an experimental model of rheumatoid arthritis, by downregulating both inflammatory and autoimmune components of the disease. Therefore, VIP has been proposed as a promising candidate alternative treatment for acute and chronic inflammatory and autoimmune diseases such as septic shock, arthritis, multiple sclerosis, Crohn disease, or autoimmune diabetes.

Animals↗
PubMed2001

Pituitary adenylate cyclase-activating polypeptide inhibits collagen-induced arthritis: an experimental immunomodulatory therapy.

Rheumatoid arthritis is a chronic, systemic, autoimmune, and inflammatory disorder that affects the synovial lining of the joints. We describe the beneficial effects of the pituitary adenylate cyclase-activating polypeptide (PACAP) in the collagen-induced arthritis experimental murine model being proposed as a novel therapeutic approach in the treatment of rheumatoid arthritis. PACAP greatly decreases arthritis frequency and severity in the studied mice by improving clinical symptoms, ameliorating joint damage, and blocking both the inflammatory and autoimmune mediators which are the main keys of the pathogenesis of this disease. With this study, PACAP emerges as a promising candidate for the treatment of a pathology with a high world incidence but currently no effective treatment.

Adjuvants, Immunologic↗
PubMed2001

Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease.

Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease of unknown etiology, characterized by chronic inflammation in the joints and subsequent destruction of the cartilage and bone. We describe here a new strategy for the treatment of arthritis: administration of the neuropeptide vasoactive intestinal peptide (VIP). Treatment with VIP significantly reduced incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. The therapeutic effect of VIP was associated with downregulation of both inflammatory and autoimmune components of the disease. Our data indicate VIP as a viable candidate for the development of treatments for RA.

Animals↗
PubMed2001

Immunology of VIP: a review and therapeutical perspectives.

Vasoactive intestinal peptide (VIP) is a neuropeptide with a broad distribution in the body that exerts very important pleiotropic functions in several systems. The present work reviews the immunology of VIP. Being daring, this neuropeptide could be included in the group of cytokines since it is produced and secreted by different immunocompetent cells in response to various immune signals, plays a broad spectrum of immunological functions, and exerts them, in a paracrine and/or autocrine way, through three different specific receptors. Although VIP has been classically considered as an immunodepressant agent, and its main described role has been as an anti-inflammatory factor, several evidences suggest that a better way to see this peptide is as a modulator of the homeostasis of the immune system. In the last decade, the pharmacology of VIP has spectacularly grown, and VIP itself, as well as more stable VIP-derived agents, have been used or proposed as efficient therapeutical treatments of several disorders, specially inflammatory and autoimmune diseases, such as septic shock, rheumatoid arthritis, multiple sclerosis, Crohn's disease and autoimmune diabetes. A broad field of perspectives is actually open, and further investigations will help us to definitively understand the immunology of this very important peptide.

Animals↗
PubMed2000

Anti-inflammatory properties of the type 1 and type 2 vasoactive intestinal peptide receptors: role in lethal endotoxic shock.

Vasoactive intestinal peptide (VIP) is a neuropeptide that can modulate several immune aspects. Previous reports showed that VIP attenuates the deleterious consequences of septic shock by inhibiting the production of pro-inflammatory agents and stimulating the production of anti-inflammatory cytokines in activated macrophages. In this study, by using selective VIP agonists, we investigated the differential involvement of the VIP receptors in the anti-inflammatory role of VIP. Both the type 1 VIP receptor (VPAC1) agonist, [K(15), R(16), L(27)] VIP 1-7-GRF 8-27, and the type 2 VIP receptor (VPAC2) agonist, Ro25-1553, protected mice from lethal endotoxemia by inhibiting the macrophage-derived pro-inflammatory mediators IL-6, TNF-alpha, IL-12 and NO, and by stimulating the production of the anti-inflammatory cytokine IL-10. In addition, both VIP and VPAC1 agonist, but not the VPAC2 agonist, reduced in vitro and in vivo the expression of the co-stimulatory B7. 1/B7.2 molecules, and the subsequent stimulatory activity for T helper cells in stimulated macrophages. The higher effectiveness of the VPAC1 agonist compared with the VPAC2 agonist suggests that VPAC1 is the major mediator of the anti-inflammatory action of VIP. Since VIP and the two agonists appear to affect multiple cytokines and inflammatory factors, they might provide a more efficient therapeutical alternative to the use of specific cytokine antibodies or antagonists.

Animals↗
PubMed2000

VIP and PACAP induce shift to a Th2 response by upregulating B7.2 expression.

VIP and PACAP, two structurally related neuropeptides produced within the lymphoid microenvironment, modulate several immunological functions. Although primarily anti-inflammatory in nature, VIP and PACAP also affect resting macrophages. In this study, we report on the role of VIP and PACAP on macrophage B7 expression and costimulatory function for antigen-primed CD4+ T cells, and on the macrophage-induced regulation of Th1/Th2 differentiation in vitro and in vivo. VIP and PACAP upregulate B7.2, but not B7.1, MHC class II, or ICAM-1 expression, and activate macrophages to stimulate the proliferation of naïve T cells in response to soluble anti-CD3 or allogeneic stimulation. The stimulatory effect is mediated through the specific receptor VPAC1, and involves the cAMP/PKA pathway as second messengers. The enhancement in B7.2 expression occurs at both mRNA and protein levels, and correlates with the VIP/PACAP induced upregulation of the costimulatory activity of macrophages for antigen-primed CD4+ T cells. VIP/PACAP-treated macrophages gain the ability to induce Th2-type cytokines such as IL-4 and IL-5, and to reduce Th1-type cytokines such as IFN gamma and IL-2. In vivo administration of VIP or PACAP in antigen-immunized mice reduces the numbers of IFN gamma-secreting cells, enhances the numbers of IL-4-secreting cells, and affects the pattern of antigen-specific Ig isotypes. The preferential differentiation into Th2 effector cells induced by VIP/PACAP-treated macrophages is mediated through the upregulation of B7.2 expression. Since Th1-dominated responses are associated with some autoimmune diseases and inflammatory reactions typical of cell-mediated immunity, the VIP/PACAP inhibition of Th1 development may represent an additional mechanism for the general anti-inflammatory activity of the two neuropeptides.

Animals↗
PubMed2000

Receptors and transcriptional factors involved in the anti-inflammatory activity of VIP and PACAP.

VIP and PACAP modulate the function of inflammatory cells through specific receptors. VIP/PACAP inhibit the production of TNF alpha, IL-6, IL-12, and nitric oxide (NO), and stimulate IL-10 in peritoneal macrophages and Raw 264.7 cells. Here we report on the specific VIP/PACAP receptors, transduction pathways, and transcriptional factors involved in the regulation of these macrophage factors by VIP and PACAP. Both neuropeptides inhibit IL-6 production mainly through PAC1 binding, PKC activation, and the subsequent shedding of the LPS receptor CD14 in macrophages. However, the effects on TNF alpha, IL-10, IL-12, and NO are mostly mediated through the constitutively expressed VPAC1 receptor, although the inducible expressed VPAC2 may also participate. VIP/PACAP binding to VPAC1 induces both a cAMP-dependent and a cAMP-independent pathways that regulate cytokine and NO production at the transcriptional level. VIP/PACAP inhibit TNF alpha through reduction in NFkB binding and changes in the composition of CRE-binding complexes; they inhibit IL-12 through reduction in NFkB binding and changes in the composition of the ets-2 complexes. VIP/PACAP inhibit iNOS expression through reduction in NFkB and IRF-1 binding, and augment IL-10 by increasing CREB-binding. Whereas the inhibition of IRF-1 and CRE-binding complexes seems to be mediated through the cAMP-dependent pathway, VIP/PACAP inhibition of NFkB nuclear translocation is mediated through a reduction in IkB alpha degradation mediated by the cAMP-independent pathway. This study provides new evidence for the understanding of the molecular mechanism by means of which VIP and PACAP attenuate the inflammatory response.

Animals↗
PubMed1999

VIP and PACAP differentially regulate the costimulatory activity of resting and activated macrophages through the modulation of B7.1 and B7.2 expression.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP), two structurally related neuropeptides produced and/or released within the lymphoid microenvironment, modulate numerous immune functions. Although primarily antiinflammatory in nature, VIP and PACAP also affect resting macrophages. In this study, we report on in vitro and in vivo dual effects of VIP/PACAP on the expression of B7.1 and B7.2 and on the costimulatory activity for T cells in unstimulated and LPS/IFN-gamma-activated macrophages. VIP and PACAP up-regulate B7.2, but not B7.1, expression and induce the capacity to stimulate the proliferation of naive T cells in response to soluble anti-CD3 or allogeneic stimulation. In contrast, both neuropeptides down-regulate B7.1/B7.2 expression on LPS/IFN-gamma-activated macrophages and inhibit the endotoxin-induced costimulatory activity for T cells. Interestingly, both the stimulatory and the inhibitory effects of VIP/PACAP are mediated through the specific receptor VPAC1 and involve the cAMP/protein kinase A transduction pathway. The dual effect on B7.1 and B7.2 expression occurs at both mRNA and protein level and correlates with the VIP/PACAP regulation of the macrophage costimulatory activity. Through their regulatory role for resting and activated macrophages, VIP and PACAP act as endogenous participants in the control of immune homeostasis. Their effects depend not only on the timing of their release, but also on the activation and differentiation state of the neighboring immune cells.

Adjuvants, Immunologic↗
PubMed1999

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide stimulate the induction of Th2 responses by up-regulating B7.2 expression.

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 mice reduce the numbers of IFN-gamma-secreting cells and enhance the numbers of IL-4-secreting cells. One of the consequences of the VIP-/PACAP-induced shift in cytokine profile is a change in the Ag-specific Ig isotype, increasing IgG1 and decreasing IgG2a levels. Finally, the preferential differentiation into Th2 effector cells after Ag stimulation induced by VIP-/PACAP-treated macrophages is mediated through the up-regulation of B7.2 expression.

Animals↗
PubMed1999

Shedding of membrane-bound CD14 from lipopolysaccharide-stimulated macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide.

Macrophage activation and deactivation play essential roles in the initiation and maintenance of a successful immune response. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP), two structurally related neuropeptides, act as macrophage deactivating factors. We reported previously that VIP and PACAP inhibit IL-6, IL-12, TNF alpha and NO production, and enhance IL-10 production, from lipopolysaccharide (LPS)-stimulated macrophages. In this study, we demonstrate that VIP and PACAP down-regulate the expression of CD14, the membrane-bound LPS receptor, by inducing its rapid shedding. The soluble CD14 released by VIP and PACAP corresponds in size to the soluble CD14 released by PMA. Neither VIP/PACAP nor PMA, affect the steady-state levels of CD14 mRNA. The CD14 shedding induced by VIP/PACAP is mediated through the PAC1 specific receptors and the major transduction pathway involves the protein kinase C (PKC). The VIP/PACAP inhibition of TNF alpha and NO occurs through both CD14-dependent and -independent mechanisms, whereas the inhibition of IL-6 production appears to be strictly CD14-dependent. The shedding of CD14 by VIP and PACAP represents an important mechanism by which these neuropeptides limit the macrophage inflammatory response.

Animals↗
PubMed1999

Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: in vitro and in vivo studies.

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-alpha 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-alpha by endotoxin-activated murine peritoneal macrophages. Both neuropeptides rapidly and specifically inhibit the LPS-stimulated production of TNF-alpha, exerting their action through the binding to VPAC1 receptor and the subsequent activation of the adenylate cyclase system. VIP and PACAP regulate the production of TNF-alpha at a transcriptional level. In vitro results were correlated with an inhibition of both TNF-alpha expression and release in endotoxemic mice in vivo. The immunomodulatory role of VIP in vivo is supported by the up-regulation of VIP release in serum and peritoneal fluid by LPS and proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. These findings support the idea that under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of TNF-alpha to reduce inflammation or shock.

Animals↗
PubMed1999

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activation polypeptide (PACAP) protect mice from lethal endotoxemia through the inhibition of TNF-alpha and IL-6.

The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) down-regulate 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 TNF-alpha and IL-6, suggesting that the protective effect is exerted by inhibiting the production of endogenous TNF-alpha/IL-6. Consistent with this mechanism, VIP does not protect against septic shock induced by exogenous TNF-alpha. 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 TNF-alpha and IL-6 production, and may offer an alternative in the treatment of human septic shock syndrome.

Animals↗
PubMed1999

Regulation of VIP production and secretion by murine lymphocytes.

Vasoactive intestinal peptide (VIP) is a neuropeptide present in the lymphoid microenvironment with a multiplicity of actions. Two sources for VIP have been described in the immune system, the terminals present in central and peripheral lymphoid organs and the immune cells. Although VIP is synthesized by lymphocytes, there is no evidence demonstrating that VIP is released, and which stimuli are able to induce VIP production and secretion. In this study, we demonstrated for the first time, that agents that mediate important immune functions, such as proliferation and antigenic stimulation (Con A, LPS, and anti-TCR antibody), inflammation (LPS, TNFalpha, IL-6 and IL-1beta) or apoptosis (dexamethasone) induce the production and release of VIP to the lymphoid microenvironment. We conclude that VIP is produced and secreted by lymphocytes and propose that during an immune response, the timely release of VIP within the lymphoid organs and peritoneum should influence the differentiation and/or downregulation of the ongoing response.

Animals↗
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↗