The Open Immunology Journal, 2009, 2, 9-41 9 Open Access Histamine, Histamine Receptors, and their Role in Immunomodulation: An Updated Systematic Review Mohammad Shahid*,1, Trivendra Tripathi2, Farrukh Sobia1, Shagufta Moin2, Mashiatullah Siddiqui2 and Rahat Ali Khan3 1Section of Immunology and Molecular Biology, Department of Microbiology, 2Department of Biochemistry, and 3Department of Pharmacology, Faculty of Medicine, Jawaharlal Nehru Medical College & Hospital, Aligarh Muslim University, Aligarh-202002, U.P., India Abstract: Histamine, a biological amine, is considered as a principle mediator of many pathological processes regulating several essential events in allergies and autoimmune diseases. It stimulates different biological activities through differen- tial expression of four types of histamine receptors (H1R, H2R, H3R and H4R) on secretion by effector cells (mast cells and basophils) through various immunological or non-immunological stimuli. Since H4R has been discovered very re- cently and there is paucity of comprehensive literature covering new histamine receptors, their antagonists/agonists, and role in immune regulation and immunomodulation, we tried to update the current aspects and fill the gap in existing litera- ture. This review will highlight the biological and pharmacological characterization of histamine, histamine receptors, their antagonists/agonists, and implications in immune regulation and immunomodulation. Keywords: Histamine, histamine receptors, H4-receptor, antagonists, agonists, immunomodulation. I. INTRODUCTION derivatives. For this noble research on antihistamines and curare, Bovet was awarded the Nobel Prize in 1957 [8]. It In historical evolution, histamine (biogenic amine) is was being documented that histamine played an important probably one of the most important phlogistic ancient media- role as a mediator of allergic reactions indicated by a series tor, and even one of the most intensely studied molecules in of compounds with antihistamine activity which protected biological systems which have been using histamine, guinea pigs from anaphylaxis. However, the clinical use of catecholamines and other chemical mediators to communi- these compounds in humans was precluded due to their tox- cate among cells [1]. Histamine was synthesized in 1907 and ™ icity [9]. The first antihistamine, Antergan (phenben- characterized in 1910 as a substance (“beta-1”) [2], owing to zamine, RP 2339) was being used in humans [10], but this its significant competence to constrict guinea pig ileum, and ™ compound was subsequently replaced by Neoantergan its cogent vasodepressor action. However, it took 17 years to (mepyramine, pyrilamine, RP 2786), which is still in use to demonstrate its presence in normal tissues [3]. The relation counteract the uncomfortable effects of histamine release in between histamine and anaphylactic reactions was made the skin. Many other antihistamines such as diphenhy- rapidly in 1929, and was identified as a mediator of anaphy- ™ dramine (Benadryl ), tripelennamine, chlorpheniramine and lactic reactions in 1932 [4, 5], whereas its connection to mast promethazine are also used in similar manner to counteract cells was not made until 1952 [6], and also its connection to the adverse effects of histamine [8]. Subsequently, after basophils in 1972 [7]. The search for compounds being po- 1945, these antihistamines were widely used in the treatment tent to neutralize the pathological effects of histamine began of various allergic diseases such as hay fever, urticaria, and at the Pasteur Institute in Paris during the 1930s, and these allergic rhinitis. However, the side effects were not uncom- compounds were found to partially block the effects of his- mon and the sedation was a drawback to their use. A very tamine based on the ethylenediamine structure. The first an- few side effects were put to their good use; therefore, some tihistamine compound was the adrenolytic benzodioxan, ™ antihistamines such as cyclizine (Marzine ) and diphenhy- piperoxan (933F), reported by Ungar, Parrot and Bovet in dramine in the form of its 8-chlorotheophyllinate (Drama- 1937 and was shown to block the effect of histamine on the ™ mine ) are being used as an antiemetics for travel sickness guinea-pig ileum [8]. It followed shortly by the report of [8]. By 1950 there were only 20 compounds clinically avail- Bovet and Staub [9] that structurally related to aryl ethers able to block the effects of histamine [1], but advances in such as the thymol ether (929F) [8]. The latter antihistamine histamine receptors (HRs) ligands have ever attracted many compound proved to be highly toxic for clinical develop- researchers for pharmaceutical developments and are still ment; however, the replacement of ether oxygen by an amino highly topical [11]. group led to the search of aniline ethylene diamine Histamine (2-(imidazol-4-yl) ethylamine) is one of the monoamines and was coined after the Greek word for tissue *Address correspondence to this author at the Department of Microbiology, histos, with the broadest spectrum of activities in various JN Medical College & Hospital, Aligarh Muslim University, Aligarh-202 physiological and pathological conditions including the cell 002, U.P., India; Tel: +91-571-2720382; Fax: +91-571-2720382; proliferation, differentiation, hematopoiesis, embryonic de- E-mail: [email protected]; [email protected] velopment, regeneration, wound healing, aminergic neuro- 1874-2262/09 2009 Bentham Open 10 The Open Immunology Journal, 2009, Volume 2 Shahid et al. transmission and numerous brain functions (sleep/noci- parietal cells, mast cells(~3 pg/cell histamine), and baso- ception, food intake and aggressive behavior), secretion of phils(~1 pg/cell histamine). Histamine has an important role pituitary hormones, regulation of gastrointestinal and circu- in human health, and exerting its diverse biologic effects by latory functions, cardiovascular system (vasodilatation and 4 types of receptors [1, 13, 20-22]. Histamine is also pro- blood pressure reduction), as well as inflammatory reactions, duced by enterochromaffin-like cells (ECL) in the stomach modulation of the immune response, energy of endocrine and plays an important role in secretion of gastric acid [14]. and homeostasis [1, 12-18]. It is being documented by sev- Only basophils and mast cells can store the amine in specific eral studies which highlighted the evidence of histamine that granules, in the hematopoietic system, where histamine is it elicits immune-modulatory and pro-inflammatory effects closely associated with anionic proteoglycans heparin (in by the differential expression of histamine receptors (H1R, mast cells) and chondroitin-4-sulfate (in basophils). In this H2R, H3R, and H4R) that is easily modulated the diverse specific form, histamine can be released in large amounts effects of histamine on immune regulation and distinct intra- during degranulation in response to various immunological cellular signals. All these four receptors are members of the (immunoglobulin E, or cytokines) or non-immunological 7-transmembrane (heptahelical) spanning family of recep- (compound 48/80, calcium ionophore, mastoparin, substance tors, are G protein-coupled (GPCR), are expressed on vari- P, opioids, or hypo-osmolar solutions) stimuli [14]. Hista- ous histamine responsive target tissues and cells and suggest mine synthesis in Golgi apparatus can be inhibited by - an important critical role of histamine in immunomodulation fluoromethylhistidin [23]. and allergic diseases [1, 8, 11-14]. Recently, many myeloid and lymphoid cell types that do In the present review, we will discuss biology of hista- not store histamine show more HDC activity and are capable mine including synthesis, regulation and metabolism; hista- of synthesis of high amounts of histamine [24]. This so mine receptors including H1-, H2-, H3-, and H4-receptors called “neo synthesized histamine,” has been shown in vari- and their cellular distribution, functional characterization, ous cells, including hematopoietic progenitors, macrophages, structural biology, and signaling mechanisms; non-classical neutrophils, platelets, dendritic cells (DCs) and T cells [14, histamine-binding sites such as cytochrome P450; and his- 25-28]. Histamine synthesis in non-mast cells was first con- tamine transporters; as well as immune regulation by hista- firmed using W/WV mice, which genetically lack mature mast mine in immunomodulation and allergic inflammation; ef- cells, upon stimulation with a phorbol ester [29]. HDC activ- fects of histamine in immune cells in respect to allergic dis- ity is demonstrated in vitro through cytokines, such as IL-1, eases; implication of histamine on cytokines production; IL-3, IL-12, IL- 18, GM-CSF, macrophage-colony stimulat- significance of histamine in autoimmunity and allergic dis- ing factor, TNF-, and calcium ionophore [30, 31]. Histidine eases and also in malignancies; and finally the relation of decarboxylase (HDC) activity has been modulated in condi- histamine-cytokine during hematopoiesis. tions such as LPS stimulation, inflammation, infection, and graft rejection, in vivo [32]. II. BIOLOGY OF HISTAMINE It is being demonstrated that the generation of HDC- Histamine exhibits two main important basic functionali- knockout mice provides histamine-free system and it is more ties such as primary aliphatic amine (pKa1 9.4) and imidazole beneficial to study the role of endogenous histamine in a (pKa2 5.8). These make the monocation