title: Histamine receptor 2 modifies dendritic cell responses to microbial ligands.
abstract: BACKGROUND
  The induction of tolerance and protective immunity to microbes is significantly influenced by host- and microbiota-derived metabolites, such as histamine.
  
  
  OBJECTIVE
  We sought to identify the molecular mechanisms for histamine-mediated modulation of pattern recognition receptor signaling.
  
  
  METHODS
  Human monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells, and plasmacytoid dendritic cells were examined. Cytokine secretion, gene expression, and transcription factor activation were measured after stimulation with microbial ligands and histamine. Histamine receptor 2 (H₂R)-deficient mice, histamine receptors, and their signaling pathways were investigated.
  
  
  RESULTS
  Histamine suppressed MDDC chemokine and proinflammatory cytokine secretion, nuclear factor κB and activator protein 1 activation, mitogen-activated protein kinase phosphorylation, and T(H)1 polarization of naive lymphocytes, whereas IL-10 secretion was enhanced in response to LPS and Pam3Cys. Histamine also suppressed LPS-induced myeloid dendritic cell TNF-α secretion and suppressed CpG-induced plasmacytoid dendritic cell IFN-α gene expression. H₂R signaling through cyclic AMP and exchange protein directly activated by cyclic AMP was required for the histamine effect on LPS-induced MDDC responses. Lactobacillus rhamnosus, which secretes histamine, significantly suppressed Peyer patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild-type but not H₂R-deficient animals.
  
  
  CONCLUSIONS
  Both host- and microbiota-derived histamine significantly alter the innate immune response to microbes through H₂R.
authors: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors: Remo
authors: R
authors: Frei
authors: Ruth
authors: R
authors: Ferstl
authors: Patrycja
authors: P
authors: Konieczna
authors: Mario
authors: M
authors: Ziegler
authors: Tunde
authors: T
authors: Simon
authors: Tulia Mateus
authors: TM
authors: Rugeles
authors: Susanne
authors: S
authors: Mailand
authors: Takeshi
authors: T
authors: Watanabe
authors: Roger
authors: R
authors: Lauener
authors: Cezmi A
authors: CA
authors: Akdis
authors: Liam
authors: L
authors: O'Mahony
mesh_terms: D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D052201:Lacticaseibacillus rhamnosus / Q000276:immunology*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D011970:Receptors, Histamine H2 / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D011970:Receptors, Histamine H2; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D006632:Histamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases