Histamine Receptor 2 is Required to Suppress Innate Immune Responses to Bacterial Ligands in Patients with Inflammatory Bowel Disease

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 (H2R). The aim of this study was to investigate the effects of histamine and H2R 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 (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. RESULTS: 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-and IL-17 T cells. CONCLUSION: 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.

Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells

“…124,125 It is not T cells, and basophils. [126][127][128] In contrast, immune activator roles of HR1 and HR4 have been shown on many cells. 128,129 HR2 has been demonstrated to play an essential role in immune regulation by Treg cells and DCs.…”

“…The diverse effects of histamine on immune regulation are due to the differential expression and regulation of four histamine receptors (HR) and their distinct intracellular signals. In particular, the discovery of reciprocal regulation of T‐cell activity by H1 and H2 receptor activation indicating histamine receptor cross‐talk with cytokines and their expression on numerous immune and inflammatory cells were demonstrated a mostly immune suppressive effects of HR2 on DC, T cells, and basophils . In contrast, immune activator roles of HR1 and HR4 have been shown on many cells .…”

Bacterial secretion of histamine within the gut influences immune responses within the lung

“…Histamine 1 receptor (H1R) is responsible for the classical immediate hypersensitivity response, whereas H2R typically antagonizes H1R‐mediated effects. H2R has been shown to modulate DC responses to microbial ligands, prevent exaggerated invariant natural killer T‐cell responses within the lung, can mediate bacterial‐derived histamine effects within the gut and dampen the severity of colitis . Histamine 3 receptor (H3R) is a neurotransmitter release controlling presynaptic receptor.…”

Histamine receptor 2 modifies iNKT cell activity within the inflamed lung

“…H 2 R can suppress a range of immune system activities such as mast cell degranulation, antibody synthesis, dendritic cell responses to TLR stimulation, T H 1 cytokine production, and T‐cell proliferation . H 2 R‐deficient mice display defects in gastric and immune regulatory functions, while mucosal expression of H 2 R is critical for immunomodulatory responses to bacterial‐derived histamine and mucosal expression of H 2 R increases in inflamed tissue . However, the influence of H 2 R on allergic lung inflammation has not been well characterized.…”