Histamine H₄ receptor activation enhances LPS-induced IL-6 production in mast cells via ERK and PI3K activation

Eur J Immunol. 2011 Jun;41(6):1764-73. doi: 10.1002/eji.201040932. Epub 2011 May 25.


The histamine H(4) receptor (H(4)R) has been implicated in numerous inflammatory functions. Here it is shown that the receptor can mediate cytokine production from mast cells. Histamine and an H(4)R agonist, JNJ 28610244, induced the production of IL-6 in mouse bone marrow (BM)-derived mast cells. This effect was blocked by two different H(4)R antagonists and was not present in H(4)R-deficient cells. In addition, histamine acting via the H(4) R potentiated LPS-induced IL-6 production. Histamine-induced IL-6 production could be blocked by inhibitors of ERK and phosphoinositide 3-kinase γ (PI3Kγ) pathways. Furthermore, it was shown that H(4)R activation can induce phosphorylation of ERK, MEK and AKT. H(4)R activation led to a rapid and transient phosphorylation of these kinases, whereas with LPS the activation occurred at later time points. When both histamine and LPS were added, the phosphorylation was evident at 5 min and persisted for at least 60 min suggesting that changes in the kinetics of kinase activation may be one mechanism driving the signaling interaction between the H(4)R and toll-like receptors. These observations suggest that the H(4)R can synergize with other inflammatory signals to potentiate cytokine production and provides mechanistic information on the role of the H(4)R in inflammation.

MeSH terms

  • Animals
  • Bone Marrow / pathology
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Histamine / immunology
  • Histamine / metabolism
  • Indoles / pharmacology
  • Inflammation
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Mast Cells / drug effects
  • Mast Cells / immunology
  • Mast Cells / metabolism*
  • Mast Cells / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 3 / immunology
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Piperazines / pharmacology
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Histamine / genetics
  • Receptors, Histamine / immunology
  • Receptors, Histamine / metabolism*
  • Receptors, Histamine H4
  • Signal Transduction / drug effects


  • Hrh4 protein, mouse
  • Indoles
  • Interleukin-6
  • Lipopolysaccharides
  • Piperazines
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Receptors, Histamine H4
  • 1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine
  • Histamine
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinase 3