ABSTRACT
Vasoactive intestinal peptide (VIP) is a neuropeptide with potent immunoregulatory properties. Reduced serum VIP levels and alterations in VIP receptors/signaling on immune cells have been associated with different inflammatory/autoimmune diseases. However, its role in autoimmune thyroid diseases (AITD) remains unknown. This study examined the interrelationship between VIP system, autoimmune background and thyroid hormones in peripheral immune cells in patients with AITD. Only Graves' disease (GD) patients showed significantly lower serum VIP levels when compared to healthy subjects and to Hashimoto's thyroiditis patients. Serum VIP levels were lower at the onset of GD, showing a significant negative correlation with thyroid hormone levels. The expression of VIP receptors, VPAC1 and VPAC2, was significantly upregulated in peripheral blood mononuclear cells (PBMC) from GD patients. There was an impairment of VIP signalling in these patients, probably attributable to a dysfunction of VPAC1 with preservation of VPAC2. The correlation between VPAC1 and thyroid hormone receptor expression in PBMC from healthy subjects was lost in GD patients. In summary, the VIP system is altered in peripheral immune cells of GD patients and this finding is associated with different thyroid hormone receptor patterns, showing a dynamic inter-regulation and a prominent role of VIP in this setting.
Subject(s)
Graves Disease/metabolism , Vasoactive Intestinal Peptide/metabolism , Adult , Female , Humans , Male , Middle Aged , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , Thyroid Hormones/metabolism , Vasoactive Intestinal Peptide/bloodABSTRACT
Vasoactive Intestinal Peptide (VIP) is an important immunomodulator of CD4+ cells in normal and pathological conditions, which exerts its anti-inflammatory and immunomodulatory actions through VPAC receptors, VPAC1 and VPAC2. Only a decrease in the expression of VPAC1 mRNA on Th cells upon activation has been reported. Thus, the deepening in the knowledge of the behavior of these receptors may contribute to the design of new therapies based on their activation and/or blockade. In this study, we describe the expression pattern, cellular location and functional role of VIP receptors during the activation of human Th cells in healthy conditions and in early arthritis (EA). The protein expression pattern of VPAC1 did not change with the activation of Th lymphocytes, whereas VPAC2 was up-regulated. In resting cells, VPAC1 was located on the plasma membrane and nucleus, whereas it only appeared in the nucleus in activated cells. VPAC2 was always found in plasma membrane location. VIP receptors signaled through a PKA-dependent pathway in both conditions, and also by a PKA-independent pathway in activated cells. Both receptors exhibit a potent immunomodulatory capacity by controlling the pathogenic profile and the activation markers of Th cells. These results highlight a novel translational view in inflammatory/autoimmune diseases.
Subject(s)
Arthritis/immunology , Lymphocyte Activation/immunology , Receptors, Vasoactive Intestinal Peptide, Type II/metabolism , Receptors, Vasoactive Intestinal Polypeptide, Type I/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Arthritis/blood , Cell Fractionation , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/metabolism , Follow-Up Studies , Humans , Middle Aged , Primary Cell Culture , Signal Transduction/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/metabolism , Up-RegulationABSTRACT
Toll-like receptors (TLRs) are a family of key proteins that permit mammals to detect microbes and endogenous molecules, which are present in body fluids, cell membranes and cytoplasm. They confer mechanisms to the host for maintaining homeostasis, activating innate immunity and inducing signals that lead to the activation of adaptive immunity. TLR signalling induces the expression of pro-inflammatory and anti-viral genes through different and intricate pathways. However, persistent signalling can be dangerous and all members of the TLR family are involved in the pathogenesis of acute and chronic inflammation, autoimmunity, allergy, cancer and aging. The pharmaceutical industry has begun intensive work developing novel immunotherapeutic approaches based on both activation and inhibition of TLR triggering. Further, clinical trials are pending to evaluate TLR agonists as novel vaccine adjuvants and for the treatment of infectious diseases, allergic diseases and asthma. Since systemic, metabolic and neuroendocrine changes are elicited by inflammation, TLR activity is susceptible of regulation by hormones and neuroendocrine factors. Neuroendocrine mediators are important players in modulating different phases of TLR regulation contributing to the endogenous control of homeostasis through local, regional and systemic routes. Vasoactive intestinal peptide (VIP) is an important signal molecule of the neuroendocrine-immune network that has recently emerged as a potential candidate for the treatment of inflammatory and autoimmune disorders by controlling innate and adaptive immunity. This review shows current advances in the understanding of TLR modulation by VIP that could contribute to the use of this natural peptide as a therapeutic tool.
Subject(s)
Drug Delivery Systems/methods , Inflammation/drug therapy , Peptides/administration & dosage , Signal Transduction/drug effects , Toll-Like Receptors/agonists , Toll-Like Receptors/antagonists & inhibitors , Vasoactive Intestinal Peptide/therapeutic use , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Models, Biological , Peptides/pharmacology , Toll-Like Receptors/metabolism , Toll-Like Receptors/physiology , Vasoactive Intestinal Peptide/pharmacologyABSTRACT
The vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide (VIP/PACAP) system is considered as a paradigm for the use of a neuroendocrine-immune mediator in therapy. We review the role of VIP in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis as a murine model of Crohn's disease. VIP treatment led to the recovery of clinical factors, the amelioration of parameters related to the recruitment and traffic of cell populations, and the balance of inflammatory mediators derived from granulocytes, antigen-presenting cells and T lymphocytes including Th1, Th2 and Th17. Finally, the most recent data validate its therapeutic role through the modulation of TLR2 and 4 receptors.
Subject(s)
Crohn Disease/drug therapy , Neurosecretory Systems/drug effects , Pituitary Adenylate Cyclase-Activating Polypeptide/immunology , Vasoactive Intestinal Peptide/pharmacology , Animals , Antigen-Presenting Cells/drug effects , Antigen-Presenting Cells/immunology , Crohn Disease/immunology , Crohn Disease/physiopathology , Disease Models, Animal , Granulocytes/drug effects , Granulocytes/immunology , Humans , Mice , Neuroimmunomodulation/drug effects , Neuroimmunomodulation/immunology , Neurosecretory Systems/immunology , Neurosecretory Systems/physiopathology , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Vasoactive Intestinal Peptide/therapeutic useABSTRACT
The contribution of VIP immune functions to the regulation of homeostasis and health is well known. Modulation of immune responses through new therapeutics is one of the main goals of physicians and scientists seeking to control inflammatory/autoimmune diseases in humans. Initial therapeutic strategies targeted adaptive immune responses; discovery of Toll-like receptors (TLR) has widened the horizon to include targeting the innate immune system. In this review we have summarized recent information about VIP modulation of TLR function, and we suggest that VIP represents a new therapeutic option in the management of several pathologies.
Subject(s)
Immunity, Innate , Toll-Like Receptors/physiology , Vasoactive Intestinal Peptide/physiology , Animals , Gene Expression/drug effects , Humans , Models, Biological , Signal Transduction/drug effects , Toll-Like Receptor 2/genetics , Toll-Like Receptor 2/physiology , Toll-Like Receptors/genetics , Vasoactive Intestinal Peptide/pharmacologyABSTRACT
Our research about VIP/PACAP and the immune system goes back to 1990 when our group described the expression of VIP on lymphocytes for the first time. Since this year, using three models of disease, septic shock, rheumathoid arthritis, and Crohn's disease, we are trying to contribute with new pieces to the puzzle of immunity to approach the use of VIP/PACAP system as a therapeutic agent. In 1999 we established that the first step in the beneficial effect of the VIP/PACAP system exerts consists in its potent anti-inflammatory action. Thus, VIP and PACAP inhibit the expression and release of proinflammatory cytokines and chemokines, and enhance the production of the anti-inflammatory factors. These effects were reported both in vitro and in vivo, are mediated by the presence of PAC1, VPAC1, and VPAC2 receptors, in the three models of diseases used. The next step was that the system favors Th2 responses versus Th1 contributing to the remission of illness as rheumatoid arthritis or Crohn's disease by blocking the autoimmune component of these diseases. Because it appears that inflammatory processes requires more than blockade of a single mediator, new therapies blocking several components of both the infection- and the autoimmunity-induced inflammation cascades should be an interesting focus of attention. In this sense, at present we are trying to dissect new aspects of the potential therapeutic of the VIP/PACAP system in the control of CC and CXC chemokine and their receptors, coagulation factors, adhesion molecules, acute phase proteins, and osteoclastogenesis mediators as well as in the modulation of the expression of Toll-like receptors. Our more recent data open a hopeful door for the therapeutic use of VIP/PACAP in humans.
Subject(s)
Immunotherapy , Pituitary Adenylate Cyclase-Activating Polypeptide/immunology , Pituitary Adenylate Cyclase-Activating Polypeptide/metabolism , Vasoactive Intestinal Peptide/immunology , Vasoactive Intestinal Peptide/metabolism , Animals , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation/therapy , Signal Transduction , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/metabolismABSTRACT
It has been demonstrated that VIP produces beneficial effects both in a murine model of rheumatoid arthritis and in human rheumatoid synovial fibroblasts through the modulation of proinflammatory mediators. Toll-like receptors (TLRs) play a key role in the immediate recognition of microbial surface components by immune cells prior to the development of adaptative microbe-specific immune responses. In this study, we demonstrate that VIP decreases lipopolysaccharide (LPS) and TNF-alpha-induced expression of TLR4 and its correlation with the production of CCL2 and CXCL8 chemokines in human synovial fibroblasts from patients with rheumatoid arthritis and osteoarthritis. Our results add a new step for the use of VIP, as a promising candidate, for the treatment of rheumatoid arthritis.
Subject(s)
Lipopolysaccharides/pharmacology , Synovial Membrane/drug effects , Synovial Membrane/metabolism , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Vasoactive Intestinal Peptide/pharmacology , Cells, Cultured , Fibroblasts , Gene Expression Regulation , Humans , Toll-Like Receptor 4/geneticsABSTRACT
Vasoactive intestinal peptide (VIP) is a potent anti-inflammatory agent with immunoregulatory properties, skewing the immune response to a Th2 pattern of cytokine production. Here, we studied the effect of treatment with VIP in the development of diabetes in nonobese diabetic (NOD) mice, an animal model of type 1 diabetes. Mice treated with VIP from 4 weeks of age did not develop diabetes and showed milder insulitis than nontreated mice. The protective mechanism of VIP was associated with a reduction in the circulating levels of Th1 cytokines. In the pancreas of VIP-treated animals, regulatory T cell markers predominate, as indicated by the upregulation of FoxP3 and transforming growth factor-beta (TGF-beta), and the downregulation of the transcription factor, T-bet. These findings indicate that VIP restores tolerance to pancreatic islets by promoting the local differentiation and function of regulatory T cells.
Subject(s)
Autoimmunity/drug effects , Autoimmunity/immunology , Immune Tolerance/drug effects , Immune Tolerance/immunology , Vasoactive Intestinal Peptide/pharmacology , Animals , Cell Proliferation/drug effects , Diabetes Mellitus/metabolism , Diabetes Mellitus/prevention & control , Female , Forkhead Transcription Factors/metabolism , Insulin/metabolism , Mice , Mice, Inbred NOD , Pancreas/drug effects , Pancreas/metabolism , Th1 Cells/cytology , Th1 Cells/drug effects , Th1 Cells/metabolism , Th2 Cells/cytology , Th2 Cells/drug effects , Th2 Cells/metabolism , Transforming Growth Factor beta/metabolismABSTRACT
OBJECTIVES: Vasoactive intestinal peptide (VIP) has demonstrated therapeutic effects in arthritis by inhibiting both innate and acquired immune responses. We investigated the potential effects of VIP in the regulation of Toll-like receptor (TLR) expression and function in synovial fibroblasts from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Cultured fibroblast-like synoviocytes (FLS) were obtained from patients with RA and OA. The effects of VIP on basal or TNF-alpha or lipopolysaccharide (LPS)-induced TLR2, TLR4 and MyD88 expression and its effects on TLR4-mediated CCL2 and CXCL8 chemokine production were studied by reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: TLR2, TLR4 and MyD88 mRNA expression was increased in RA FLS compared with OA FLS. The largest increase was observed for TLR4 and there was also overexpression at the protein level in RA FLS. TLR4 and MyD88 mRNA and proteins were induced by LPS and TNF-alpha in RA FLS. VIP down-regulated the induced but not the constitutive expression of TLR4 and MyD88 in RA FLS. VIP treatment decreased CCL2 and CXCL8 chemokine production in response to TLR4 activation with LPS in RA FLS. CONCLUSIONS: We demonstrate that VIP down-regulates LPS and TNF-alpha activation of TLR4 expression and the TLR4 functional response in terms of proinflammatory chemokine production. These studies suggest that the pleiotropic anti-inflammatory actions of VIP involve inhibitory effects on TLR4 expression and signalling.
