Regulation of the immune response and inflammation by histamine and histamine receptors
2011; Elsevier BV; Volume: 128; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2011.06.051
ISSN1097-6825
AutoresLiam O’Mahony, Mübeccel Akdiş, Cezmi A. Akdiş,
Tópico(s)Circadian rhythm and melatonin
ResumoHistamine is a biogenic amine with extensive effects on many cell types, including important immunologic cells, such as antigen-presenting cells, natural killer cells, epithelial cells, and T and B lymphocytes. Histamine and its 4 receptors represent a complex system of immunoregulation with distinct effects dependent on receptor subtypes and their differential expression. These are influenced by the stage of cell differentiation, as well as microenvironmental influences, leading to the selective recruitment of effector cells into tissue sites accompanied by effects on cellular maturation, activation, polarization, and effector functions, which lead to tolerogenic or proinflammatory responses. In this review we discuss the regulation of histamine secretion, receptor expression, and differential activation of cells within both the innate and adaptive immune responses. It is clear that the effects of histamine on immune homeostasis are dependent on the expression and activity of the 4 currently known histamine receptors, and we also recognize that 100 years after the original identification of this biogenic amine, we still do not fully understand the complex regulatory interactions between histamine and the host immune response to everyday microbial and environmental challenges. Histamine is a biogenic amine with extensive effects on many cell types, including important immunologic cells, such as antigen-presenting cells, natural killer cells, epithelial cells, and T and B lymphocytes. Histamine and its 4 receptors represent a complex system of immunoregulation with distinct effects dependent on receptor subtypes and their differential expression. These are influenced by the stage of cell differentiation, as well as microenvironmental influences, leading to the selective recruitment of effector cells into tissue sites accompanied by effects on cellular maturation, activation, polarization, and effector functions, which lead to tolerogenic or proinflammatory responses. In this review we discuss the regulation of histamine secretion, receptor expression, and differential activation of cells within both the innate and adaptive immune responses. It is clear that the effects of histamine on immune homeostasis are dependent on the expression and activity of the 4 currently known histamine receptors, and we also recognize that 100 years after the original identification of this biogenic amine, we still do not fully understand the complex regulatory interactions between histamine and the host immune response to everyday microbial and environmental challenges. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: December 2011. Credit may be obtained for these courses until November 30, 2013.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Liam O'Mahony, PhD, Mübeccel Akdis, MD, PhD, and Cezmi A. Akdis, MDActivity Objectives1.To discuss the 4 histamine receptors (H1R-H4R) and understand the complex nature of each receptor's expression, activation, and signaling.2.To understand the effects of histamine on cells of the immune system.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: L. O'Mahony is a consultant for Alimentary Health Ltd. M. Akdis has received research support from the Swiss National Foundation and the European Union. C. A. Akdis has received research support from Novartis, Stallergenes, the Swiss National Science Foundation, the Global Allergy and Asthma European Network, and the Christine Kühne Center for Allergy Research; has served as a legal consultant/expert witness on the topics of Actellion TH2-specific receptors, Aventis T-cell, B-cell regulation, and Allergopharma Allergen–specific immunotherapy; is a Fellow and Interest Group member of the American Academy of Allergy, Asthma & Immunology; is Vice President of the European Academy of Allergy and Clinical Immunology; and is an ex-committee member and WP leader for the Global Allergy and Asthma Network (GA2LEN). Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: December 2011. Credit may be obtained for these courses until November 30, 2013. Copyright Statement: Copyright © 2011-2013. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Liam O'Mahony, PhD, Mübeccel Akdis, MD, PhD, and Cezmi A. Akdis, MD Activity Objectives1.To discuss the 4 histamine receptors (H1R-H4R) and understand the complex nature of each receptor's expression, activation, and signaling.2.To understand the effects of histamine on cells of the immune system. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: L. O'Mahony is a consultant for Alimentary Health Ltd. M. Akdis has received research support from the Swiss National Foundation and the European Union. C. A. Akdis has received research support from Novartis, Stallergenes, the Swiss National Science Foundation, the Global Allergy and Asthma European Network, and the Christine Kühne Center for Allergy Research; has served as a legal consultant/expert witness on the topics of Actellion TH2-specific receptors, Aventis T-cell, B-cell regulation, and Allergopharma Allergen–specific immunotherapy; is a Fellow and Interest Group member of the American Academy of Allergy, Asthma & Immunology; is Vice President of the European Academy of Allergy and Clinical Immunology; and is an ex-committee member and WP leader for the Global Allergy and Asthma Network (GA2LEN). GlossaryAQUAPORINProteins that function as transmembrane water channels.CD25Binds to IL-2, also known as IL-2 receptor α chain.CPGAn unmethylated DNA motif located on bacteria and DNA viruses that is a ligand for TLR9.ENTEROCHROMAFFINEpithelial cells of the intestinal mucosa that stain especially with chromium salts. They often contain serotonin.IL-2A cytokine that promotes clonal T-cell proliferation, as well as acting as a growth factor for regulatory T cells. IL-2 is also involved in activation of multiple other immune cells, including natural killer cells.LANGERHANS CELLSA subset of dendritic cells found in the epithelia and skin draining lymph nodes. Because of their long cytoplasmic processes, Langerhans cells occupy as much as 25% of the surface area of the epidermis, even though they constitute less than 1% of the cell population.NITRIC OXIDEA factor released from endothelial cells that causes vasodilation by relaxing vascular smooth muscle cells.NOCICEPTIVEResponsive to a painful or injurious stimulus.PARIETAL CELLA cell in the gastric mucosa that secretes hydrochloric acid.PLASMACYTOID DENDRITIC CELLS (DCs)A type of DC with a distinct histologic morphology that can produce high levels of type I interferon. They are thought to play special roles in antiviral host defense and autoimmunity.SPLICE VARIANTSSingle-base mutations resulting in a base change at or near an mRNA splice junction, resulting in skipped exons or premature truncation of the protein.TH9A TH2-related family of lymphocytes that produce high levels of IL-4 and IL-9.TH17A TH family induced by IL-23 and IL-6 that is involved in defense against extracellular bacteria.TH22A population of lymphocytes found in the skin of a variety of inflammatory dermatologic conditions, such as psoriasis and atopic dermatitis. They are thought to play a role in wound healing.TOLL-LIKE RECEPTOR 3 (TLR3)A TLR located on endosomal membranes that binds to double-stranded RNA from viruses.The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary. Proteins that function as transmembrane water channels. Binds to IL-2, also known as IL-2 receptor α chain. An unmethylated DNA motif located on bacteria and DNA viruses that is a ligand for TLR9. Epithelial cells of the intestinal mucosa that stain especially with chromium salts. They often contain serotonin. A cytokine that promotes clonal T-cell proliferation, as well as acting as a growth factor for regulatory T cells. IL-2 is also involved in activation of multiple other immune cells, including natural killer cells. A subset of dendritic cells found in the epithelia and skin draining lymph nodes. Because of their long cytoplasmic processes, Langerhans cells occupy as much as 25% of the surface area of the epidermis, even though they constitute less than 1% of the cell population. A factor released from endothelial cells that causes vasodilation by relaxing vascular smooth muscle cells. Responsive to a painful or injurious stimulus. A cell in the gastric mucosa that secretes hydrochloric acid. A type of DC with a distinct histologic morphology that can produce high levels of type I interferon. They are thought to play special roles in antiviral host defense and autoimmunity. Single-base mutations resulting in a base change at or near an mRNA splice junction, resulting in skipped exons or premature truncation of the protein. A TH2-related family of lymphocytes that produce high levels of IL-4 and IL-9. A TH family induced by IL-23 and IL-6 that is involved in defense against extracellular bacteria. A population of lymphocytes found in the skin of a variety of inflammatory dermatologic conditions, such as psoriasis and atopic dermatitis. They are thought to play a role in wound healing. A TLR located on endosomal membranes that binds to double-stranded RNA from viruses. The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary. The immune response is governed by strict effector and regulatory processes that normally result in protection from infection and tolerance of innocuous environmental antigens. However, in patients with inflammatory diseases, the activated immune response results in a chronic proinflammatory state characterized by activated innate pathways with aberrant expansion and polarization of TH1, TH2, TH9, TH17, TH22, or regulatory T (Treg) lymphocyte populations. Thus the identification of appropriate controlling factors that augment protective immune responses while limiting tissue damage is urgently required. Many cellular metabolites influence immune reactivity (eg, retinoic acid), and one factor that is receiving more attention as an immunomodulator is histamine (2-[4-imidazolyl]-ethylamine).1Jutel M. Akdis M. Akdis C.A. Histamine, histamine receptors and their role in immune pathology.Clin Exp Allergy. 2009; 39: 1786-1800Crossref PubMed Scopus (82) Google Scholar, 2Westly E. Nothing to sneeze at.Nat Med. 2010; 16: 1063-1065Crossref PubMed Scopus (8) Google Scholar This short-acting endogenous amine, which is widely distributed throughout the body, is synthesized by histidine decarboxylase (HDC), which decarboxylates the semiessential amino acid L-histidine. Originally discovered at the beginning of the 20th century, histamine was first chemically synthesized by Windaus and Vogt in 1907. Soon afterward, in 1910, the first biological functions of histamine were reported by Dale and Laidlaw. These authors recognized that histamine had the ability to mimic smooth muscle–stimulating and vasodepressor action previously observed during anaphylaxis.3Barger G. Dale H.H. Chemical structure and sympathomimetic action of amines.J Physiol. 1910; 41: 19-59PubMed Google Scholar, 4Dale H.H. Laidlaw P.P. The physiological action of beta-iminazolylethylamine.J Physiol. 1910; 41: 318-344PubMed Google Scholar Histamine was isolated from liver and lung tissue in 1927 before purification from other tissues succeeded and gave histamine its name based on the Greek word histos, which means tissue. Histamine is produced by a wide variety of cell types and is involved in many physiological functions, including cell proliferation and differentiation, hematopoiesis, embryonic development, regeneration, and wound healing.5Akdis C.A. Blaser K. Histamine in the immune regulation of allergic inflammation.J Allergy Clin Immunol. 2003; 112: 15-22Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 6Jutel M. Watanabe T. Akdis M. Blaser K. Akdis C.A. Immune regulation by histamine.Curr Opin Immunol. 2002; 14: 735-740Crossref PubMed Scopus (145) Google Scholar, 7Dy M. Schneider E. Histamine-cytokine connection in immunity and hematopoiesis.Cytokine Growth Factor Rev. 2004; 15: 393-410Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 8Schneider E. Rolli-Derkinderen M. Arock M. Dy M. Trends in histamine research: new functions during immune responses and hematopoiesis.Trends Immunol. 2002; 23: 255-263Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 9MacGlashan Jr., D. Histamine: a mediator of inflammation.J Allergy Clin Immunol. 2003; 112: S53-S59Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar Mast cells, basophils, gastric enterochromaffin–like cells, and histaminergic neurons are the best-described cellular sources of histamine, but other cell types, such as platelets, dendritic cells (DCs), and T cells, can also express HDC after stimulation. HDC expression is influenced by cytokines, including IL-1, IL-3, IL-12, IL-18, GM-CSF, macrophage colony-stimulating factor, and TNF-α.1Jutel M. Akdis M. Akdis C.A. Histamine, histamine receptors and their role in immune pathology.Clin Exp Allergy. 2009; 39: 1786-1800Crossref PubMed Scopus (82) Google Scholar, 10Yoshimoto T. Tsutsui H. Tominaga K. Hoshino K. Okamura H. Akira S. et al.IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils.Proc Natl Acad Sci U S A. 1999; 96: 13962-13966Crossref PubMed Scopus (302) Google Scholar Mast cells and basophils store large quantities of histamine, which is released on degranulation in response to immunologic and nonimmunologic stimuli. However, other cell types, such as DCs and lymphocytes, do not store histamine intracellularly but secrete it after synthesis.11Saxena S.P. McNicol A. Brandes L.J. Becker A.B. Gerrard J.M. Histamine formed in stimulated human platelets is cytoplasmic.Biochem Biophys Res Commun. 1989; 164: 164-168Crossref PubMed Scopus (12) Google Scholar, 12Kubo Y. Nakano K. Regulation of histamine synthesis in mouse CD4+ and CD8+ T lymphocytes.Inflamm Res. 1999; 48: 149-153Crossref PubMed Scopus (45) Google Scholar, 13Radvany Z. Darvas Z. Kerekes K. Prechl J. Szalai C. Pallinger E. et al.H1 histamine receptor antagonist inhibits constitutive growth of Jurkat T cells and antigen-specific proliferation of ovalbumin-specific murine T cells.Semin Cancer Biol. 2000; 10: 41-45Crossref PubMed Scopus (30) Google Scholar Although histamine is well recognized for its effects in the immediate-type hypersensitivity response (ie, increased vascular permeability, smooth muscle contraction, activation of nociceptive nerves, wheal-and-flare reaction, and itch response), the pathological relevance of increased histamine levels at diseased sites is less well understood in other disorders, such as inflammatory bowel disease and irritable bowel syndrome.14He S.H. Key role of mast cells and their major secretory products in inflammatory bowel disease.World J Gastroenterol. 2004; 10: 309-318Crossref PubMed Google Scholar, 15Buhner S. Li Q. Vignali S. Barbara G. De Giorgio R. Stanghellini V. et al.Activation of human enteric neurons by supernatants of colonic biopsy specimens from patients with irritable bowel syndrome.Gastroenterology. 2009; 137: 1425-1434Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar Indeed, histamine might negatively or positively influence parasitic or bacterial infections.16Beghdadi W. Porcherie A. Schneider B.S. Dubayle D. Peronet R. Huerre M. et al.Inhibition of histamine-mediated signaling confers significant protection against severe malaria in mouse models of disease.J Exp Med. 2008; 205: 395-408Crossref PubMed Scopus (43) Google Scholar, 17Metz M. Doyle E. Bindslev-Jensen C. Watanabe T. Zuberbier T. Maurer M. Effects of antihistamines on innate immune responses to severe bacterial infection in mice.Int Arch Allergy Immunol. 2011; 155: 355-360Crossref PubMed Scopus (10) Google Scholar Cells of both the innate and adaptive immune response can be regulated by histamine.5Akdis C.A. Blaser K. Histamine in the immune regulation of allergic inflammation.J Allergy Clin Immunol. 2003; 112: 15-22Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 6Jutel M. Watanabe T. Akdis M. Blaser K. Akdis C.A. Immune regulation by histamine.Curr Opin Immunol. 2002; 14: 735-740Crossref PubMed Scopus (145) Google Scholar, 18Jutel M. Watanabe T. Klunker S. Akdis M. Thomet O.A. Malolepszy J. et al.Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors.Nature. 2001; 413: 420-425Crossref PubMed Scopus (379) Google Scholar, 19Banu Y. Watanabe T. Augmentation of antigen receptor-mediated responses by histamine H1 receptor signaling.J Exp Med. 1999; 189: 673-682Crossref PubMed Scopus (89) Google Scholar, 20Ash A.S. Schild H.O. Receptors mediating some actions of histamine.Br J Pharmacol Chemother. 1966; 27: 427-439Crossref PubMed Google Scholar These cells express histamine receptors (HRs) and under certain circumstances can also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization, and effector functions, leading to tolerogenic or proinflammatory responses. In this review we discuss HR expression and differential activation of cells within both the innate and adaptive immune response and the signal transduction mechanisms that influence their activity. The regulatory nature of histamine in immunology is dependent on its binding to 4 subtypes of HRs, which are named chronologically in order of their discovery: H1R to H4R. Although it had been suspected for a long time that more than 1 HR existed based on functional observations, the first definitive differentiation between H1R and H2R was described in 1966,20Ash A.S. Schild H.O. Receptors mediating some actions of histamine.Br J Pharmacol Chemother. 1966; 27: 427-439Crossref PubMed Google Scholar H3R was identified in 1999,21Lovenberg T.W. Roland B.L. Wilson S.J. Jiang X. Pyati J. Huvar A. et al.Cloning and functional expression of the human histamine H3 receptor.Mol Pharmacol. 1999; 55: 1101-1107Crossref PubMed Scopus (0) Google Scholar and the fourth receptor was designated H4R in 2000.22Oda T. Morikawa N. Saito Y. Masuho Y. Matsumoto S. Molecular cloning and characterization of a novel type of histamine receptor preferentially expressed in leukocytes.J Biol Chem. 2000; 275: 36781-36786Crossref PubMed Scopus (452) Google Scholar These 4 receptors belong to the rhodopsin-like family of G protein–coupled receptors (GPCR), which are differentially expressed in numerous cell types and contain 7 transmembrane domains.7Dy M. Schneider E. Histamine-cytokine connection in immunity and hematopoiesis.Cytokine Growth Factor Rev. 2004; 15: 393-410Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 23Akdis C.A. Simons F.E. Histamine receptors are hot in immunopharmacology.Eur J Pharmacol. 2006; 533: 69-76Crossref PubMed Scopus (129) Google Scholar Receptor diversity has been confirmed by means of pharmacologic studies and by their low protein homology, which is suggestive of their evolution from different ancestral genes.24Leurs R. Hoffmann M. Wieland K. Timmerman H. H3 receptor gene is cloned at last.Trends Pharmacol Sci. 2000; 21: 11-12Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar For example, H1R and H2R are approximately 35% homologous, whereas H3R and H4R are more closely related. HR antagonists can be cross-reactive with other GPCRs (eg, anticholinergic effects of H1R antagonists), which is a potential explanation for the side effects, such as obesity and appetite stimulation, of the H1R antagonists. However, this has not been proved in vivo. In addition, there is cross-reactivity between antipsychotic and tetracyclic antidepressants with H1R and H4R, although the same study showed that the current H1R antagonists did not bind H4R, at least not with high affinity.25Lim H.D. van Rijn R.M. Ling P. Bakker R.A. Thurmond R.L. Leurs R. Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist.J Pharmacol Exp Ther. 2005; 314: 1310-1321Crossref PubMed Scopus (170) Google Scholar H1R is encoded by an intronless gene, which is located on chromosome 3p25 and contains 487 amino acids. The 56-kd H1R is expressed by a broad range of cell types, including neurons, airway and vascular smooth muscle cells, hepatocytes, chondrocytes, endothelial cells, DCs, monocytes, neutrophils, and T and B cells.26Haas H. Panula P. The role of histamine and the tuberomamillary nucleus in the nervous system.Nat Rev Neurosci. 2003; 4: 121-130Crossref PubMed Scopus (459) Google Scholar, 27Togias A. H1-receptors: localization and role in airway physiology and in immune functions.J Allergy Clin Immunol. 2003; 112: S60-S68Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 28Smit M.J. Hoffmann M. Timmerman H. Leurs R. Molecular properties and signalling pathways of the histamine H1 receptor.Clin Exp Allergy. 1999; 29: 19-28PubMed Google Scholar, 29Leurs R. Smit M.J. Meeder R. Ter Laak A.M. Timmerman H. Lysine200 located in the fifth transmembrane domain of the histamine H1 receptor interacts with histamine but not with all H1 agonists.Biochem Biophys Res Commun. 1995; 214: 110-117Crossref PubMed Scopus (34) Google Scholar H1R gene expression can be upregulated by IL-3, IL-4, and histamine.30Horio S. Fujimoto K. Mizuguchi H. Fukui H. Interleukin-4 up-regulates histamine H1 receptors by activation of H1 receptor gene transcription.Naunyn Schmiedebergs Arch Pharmacol. 2010; 381: 305-313Crossref PubMed Scopus (6) Google Scholar H1R activation results in airway and vascular smooth muscle cell contraction, increased vascular endothelial cell permeability, synthesis of prostacyclin and platelet-activating factor, and release of von Willebrand factor and nitric oxide.29Leurs R. Smit M.J. Meeder R. Ter Laak A.M. Timmerman H. Lysine200 located in the fifth transmembrane domain of the histamine H1 receptor interacts with histamine but not with all H1 agonists.Biochem Biophys Res Commun. 1995; 214: 110-117Crossref PubMed Scopus (34) Google Scholar, 31Leurs R. Church M.K. Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.Clin Exp Allergy. 2002; 32: 489-498Crossref PubMed Scopus (244) Google Scholar, 32Akdis M. Verhagen J. Taylor A. Karamloo F. Karagiannidis C. Crameri R. et al.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.J Exp Med. 2004; 199: 1567-1575Crossref PubMed Scopus (632) Google Scholar Typical immediate hypersensitivity responses of allergic reactions, such as redness, itching, and swelling, are the result of H1R activation. Rhinorrhea, bronchoconstriction, anaphylaxis, conjunctivitis, and urticaria are important peripheral H1R-mediated effects, whereas central associated H1R effects include the regulation of food and water intake, convulsion, attention, and sleep regulation.27Togias A. H1-receptors: localization and role in airway physiology and in immune functions.J Allergy Clin Immunol. 2003; 112: S60-S68Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 31Leurs R. Church M.K. Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects.Clin Exp Allergy. 2002; 32: 489-498Crossref PubMed Scopus (244) Google Scholar, 33Haas H.L. Sergeeva O.A. Selbach O. Histamine in the nervous system.Physiol Rev. 2008; 88: 1183-1241Crossref PubMed Scopus (337) Google Scholar H1R signaling can antagonize or amplify H2R-mediated responses depending on the time and context of receptor activation.34Baudry M. Martres M.P. Schwartz J.C. H1 and H2 receptors in the histamine-induced accumulation of cyclic AMP in guinea pig brain slices.Nature. 1975; 253: 362-364Crossref PubMed Google Scholar, 35Garbarg M. Schwartz J.C. Synergism between histamine H1- and H2-receptors in the cAMP response in guinea pig brain slices: effects of phorbol esters and calcium.Mol Pharmacol. 1988; 33: 38-43PubMed Google Scholar Murine H1R knockout models have revealed significant immunologic (impairment of T- and B-cell responses), metabolic, and behavioral abnormalities.36Masaki T. Yoshimatsu H. The hypothalamic H1 receptor: a novel therapeutic target for disrupting diurnal feeding rhythm and obesity.Trends Pharmacol Sci. 2006; 27: 279-284Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 37Huang Z.L. Mochizuki T. Qu W.M. Hong Z.Y. Watanabe T. Urade Y. et al.Altered sleep-wake characteristics and lack of arousal response to H3 receptor antagonist in histamine H1 receptor knockout mice.Proc Natl Acad Sci U S A. 2006; 103: 4687-4692Crossref PubMed Scopus (83) Google Scholar, 38Hirai T. Okuma C. Harada C. Mio M. Ohtsu H. Watanabe T. et al.Development of amygdaloid kindling in histidine decarboxylase-deficient and histamine H1 receptor-deficient mice.Epilepsia. 2004; 45: 309-313Crossref PubMed Scopus (18) Google Scholar The human H2R is a 40-kd 359-amino-acid protein encoded by an intronless gene located on chromosome 5q35.5, and human H2R shows a high sequence homology (83% to 95% identity) to other species (guinea pig, mouse, rat, and dog).39Traiffort E. Vizuete M.L. Tardivel-Lacombe J. Souil E. Schwartz J.C. Ruat M. The guinea pig histamine H2 receptor: gene cloning, tissue expression and chromosomal localization of its human counterpart.Biochem Biophys Res Commun. 1995; 211: 570-577Crossref PubMed Scopus (36) Google Scholar, 40Kobayashi T. Inoue I. Jenkins N.A. Gilbert D.J. Copeland N.G. Watanabe T. Cloning, RNA expression, and chromosomal location of a mouse histamine H2 receptor gene.Genomics. 1996; 37: 390-394Crossref PubMed Scopus (26) Google Scholar Similar to H1R, expression of H2R is found in a variety of tissues and cells, including the brain, gastric parietal cells, smooth muscle cells, T and B cells, DCs, and cardiac tissue. H2R exhibits spontaneous and constitutive activity.41Smit M.J. Leurs R. Alewijnse A.E. Blauw J. Van Nieuw Amerongen G.P. Van De Vrede Y. et al.Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.Proc Natl Acad Sci U S A. 1996; 93: 6802-6807Crossref PubMed Scopus (159) Google Scholar In contrast to H1R, the absence of histamine can promote downregulation of H2R in a tissue-specific manner.42Fitzsimons C.P. Lazar-Molnar E. Tomoskozi Z. Buzas E. Rivera E.S. Falus A. Histamine deficiency induces tissue-specific down-regulation of histamine H2 receptor expression in histidine decarboxylase knockout mice.FEBS Lett. 2001; 508: 245-248Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar As mentioned above, H2R can antagonize certain H1R effects; for example, H2R is responsible for relaxation of smooth muscle cells in the blood vessels, uterus, and airways. In addition, H2R can modulate a range of immune system activities, such as mast cell degranulation, antibody synthesis, TH1 cytokine production, and T-cell proliferation.6Jutel M. Watanabe T. Akdis M. Blaser K. Akdis C.A. Immune regulation by histamine.Curr Opin Immunol. 2002; 14: 735-740Crossref PubMed Scopus (145) Google Scholar, 43Meiler
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