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Instituto de Parasitologia y Biomedicina, Consejo Superior de Investigaciones Cientificas, Granada, Spain (M.D.); Departamento de Bioquimica Médica y Biologia Molecular, Universidad de Sevilla, Sevilla, Spain (D.P.); and Department of Biological Sciences, Rutgers University, Newark, New Jersey (D.G.)
Abstract
Abstract I. Introduction II. Presence of Vasoactive Intestinal Peptide in the Immune System A. Historical Background: Discovery of Vasoactive Intestinal Peptide B. Vasoactive Intestinal Peptide Gene and Protein Structure C. Neuronal Vasoactive Intestinal Peptide Sources within Lymphoid Organs D. Vasoactive Intestinal Peptide Production by Immune Cells 1. Vasoactive Intestinal Peptide Production by Mast Cells and Granulocytes. 2. Vasoactive Intestinal Peptide Production by Lymphocytes. E. Mechanisms for Vasoactive Intestinal Peptide Release in the Immune System III. Vasoactive Intestinal Peptide Receptor Expression in the Immune System A. Introduction and Nomenclature B. Biochemical, Pharmacological, and Signaling Key Features of Vasoactive Intestinal Peptide Receptors C. Basis of Vasoactive Intestinal Peptide Signaling in the Immune System 1. Functional and Molecular Expression of Vasoactive Intestinal Peptide Receptors in Immune Cells. a. Vasoactive Intestinal Peptide Binding Sites in Immune Cells. b. Vasoactive Intestinal Peptide Receptor mRNA Expression in Immune Cells. 2. Vasoactive Intestinal Peptide Signaling Pathways in Immune Cells. IV. Effects of Vasoactive Intestinal Peptide on Innate Immunity A. Adaptive/Innate Immunity B. Vasoactive Intestinal Peptide Effects on Macrophages as Participants in Innate Immunity 1. Vasoactive Intestinal Peptide Effects on Macrophage Phagocytosis, Adherence, Migration, and Superoxide Ion Production. 2. Vasoactive Intestinal Peptide Effects on Macrophage-Derived Inflammatory Mediators. 3. Molecular Mechanisms Involved in the Anti-Inflammatory Action of Vasoactive Intestinal Peptide. 4. Vasoactive Intestinal Peptide Effects on Macrophage-Derived Chemokines. C. Vasoactive Intestinal Peptide Effects on Macrophages as a Link to Adaptive Immunity D. Vasoactive Intestinal Peptide Effects on Hematopoiesis V. Effects of Vasoactive Intestinal Peptide on Adaptive Immunity A. Vasoactive Intestinal Peptide Effects on T Cell Activation B. Vasoactive Intestinal Peptide Effects on CD4+ T Cell Differentiation 1. Molecular Mechanisms by which Vasoactive Intestinal Peptide Promotes Th2-Type Immune Response. C. Effects of Vasoactive Intestinal Peptide on CD4+ and CD8+ T Cell Function 1. T Cell Traffic and Adhesion. 2. CD4+ T Cell Function: Production of Cytokines. a. Th1 Cytokines: Interleukin-2 and Interferon {gamma}. b. Th2 Cytokines: Interleukin-4 and Interleukin-5. c. In Vivo Consequences of the Vasoactive Intestinal Peptide Alteration of the T Helper 1/T Helper 2 Balance. 3. Function of Cytotoxic T Cells. D. Effects of Vasoactive Intestinal Peptide on the Survival of CD4+ T Effectors E. Vasoactive Intestinal Peptide Favors the Directional Migration of T Helper 2 Cells through Effects on Chemokines VI. Effects of Vasoactive Intestinal Peptide in Brain Inflammation and Neurodegeneration VII. Clinical Implications A. Septic Shock B. Rheumatoid Arthritis C. Crohn's Disease D. Parkinson's Disease E. Brain Trauma VIII. Conclusions and Perspectives
First identified by Said and Mutt some 30 years ago, the vasoactive intestinal peptide (VIP) was originally isolated as a vasodilator peptide. Subsequently, its biochemistry was elucidated, and within the 1st decade, their signature features as a neuropeptide became consolidated. It did not take long for these insights to permeate the field of immunology, out of which surprising new attributes for VIP were found in the last years. VIP is rapidly transforming into something more than a mere hormone. In evolving scientifically from a hormone to a novel agent for modifying immune function and possibly a cytokine-like molecule, VIP research has engaged many physiologists, molecular biologists, biochemists, endocrinologists, and pharmacologists and it is a paradigm to explore mutual interactions between neural and neuroendocrine links in health and disease. The aim of this review is firstly to update our knowledge of the cellular and molecular events relevant to VIP function on the immune system and secondly to gather together recent data that support its role as a type 2 cytokine. Recognition of the central functions VIP plays in cellular processes is focusing our attention on this "very important peptide" as exciting new candidates for therapeutic intervention and drug development.
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