Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease.
Histamine is a key immunoregulatory mediator in immediate-type hypersensitivity reactions and chronic inflammatory responses, in particular histamine suppresses proinflammatory responses to bacterial ligands, through histamine receptor 2 (H2R). The aim of this study was to investigate the effects of histamine and H2R on bacteria-induced inflammatory responses in patients with IBD.



Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Crohn's disease, patients with ulcerative colitis, and healthy controls. PBMC histamine receptor expression was evaluated by flow cytometry. Cytokine secretion following Toll-like receptor (TLR)-2, TLR-4, TLR-5, or TLR-9 stimulation in the presence or absence of histamine or famotidine (H2R antagonist) was quantified. Biopsy histamine receptor gene expression was evaluated using reverse transcription-polymerase chain reaction. The in vivo role of H2R was evaluated in the T-cell transfer murine colitis model.



The percentage of circulating H2R monocytes was significantly reduced in patients with IBD. Histamine effectively suppressed TLR-induced cytokine secretion from healthy volunteer PBMCs but not for PBMCs from patients with IBD. Famotidine reversed this suppressive effect. H1R, H2R, and H4R gene expression was increased in inflamed gastrointestinal mucosa compared with noninflamed mucosa from the same patient and expression levels correlated with proinflammatory cytokine gene expression. Mice receiving lymphocytes from H2R donors, or treated with famotidine, displayed more severe weight loss, higher disease scores and increased numbers of mucosal IFN-γ and IL-17 T cells.



Patients with IBD display dysregulated expression of histamine receptors, with diminished anti-inflammatory effects associated with H2R signaling. Deliberate manipulation of H2R signaling may suppress excessive TLR responses to bacteria within the gut.
*Department of Clinical Immunology, Wroclaw Medical University, Wroclaw, Poland; †"ALL-MED" Medical Research Institute, Wroclaw, Poland; ‡Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; §Alimentary Health Pharma Davos, Davos, Switzerland; and ¶Christine Kühne-Center for Allergy Research and Education, Zurich, Switzerland.
Sylwia
S
Smolinska
David
D
Groeger
Noelia Rodriguez
NR
Perez
Elisa
E
Schiavi
Ruth
R
Ferstl
Remo
R
Frei
Patrycja
P
Konieczna
Cezmi A
CA
Akdis
Marek
M
Jutel
Liam
L
OʼMahony
D000328:Adult; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology*; D016207:Cytokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D015738:Famotidine / Q000494:pharmacology; D005260:Female; D005408:Flagellin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000235:genetics; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000074040:Receptors, Histamine H4 / Q000235:genetics; D012720:Severity of Illness Index; D018417:Th1 Cells; D058504:Th17 Cells; D051193:Toll-Like Receptors / Q000378:metabolism; D015431:Weight Loss; D055815:Young Adult
D016207:Cytokines; D006635:Histamine H2 Antagonists; D008024:Ligands; D008070:Lipopolysaccharides; D008074:Lipoproteins; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D000074040:Receptors, Histamine H4; D051193:Toll-Like Receptors; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D005408:Flagellin; D015738:Famotidine; D006632:Histamine