Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease. Issue 7 (July 2016)

• Record Type: Journal Article
• Authors: Smolinska, Sylwia; Groeger, David; Perez, Noelia Rodriguez; Schiavi, Elisa; Ferstl, Ruth; Frei, Remo; Konieczna, Patrycja; Akdis, Cezmi A.; Jutel, Marek; O'Mahony, Liam
• Is Part Of: Inflammatory bowel diseases. Volume 22:Issue 7(2016:Jul.)
• Publication Date: 2016-07
• Subjects: histamine -- IBD -- TLR; Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1097/MIB.0000000000000825
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract : Background: 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 (H2 R). The aim of this study was to investigate the effects of histamine and H2 R on bacteria-induced inflammatory responses in patients with IBD. Methods: 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 (H2 R antagonist) was quantified. Biopsy histamine receptor gene expression was evaluated using reverse transcription–polymerase chain reaction. The in vivo role of H2 R was evaluated in the T-cell transfer murine colitis model. Results: The percentage of circulating H2 R + 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. H1 R, H2 R, and H4 R 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 H2 R −/− 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. Conclusion: Patients with IBD display dysregulated expression of histamine receptors, with diminished anti-inflammatory effects associated with H2 R signaling. Deliberate manipulation of H2 R signaling may suppress excessive TLR responses to bacteria within the gut. Abstract : Supplemental Digital Content is Available in the Text.Article first published online 7 June 2016.