title: Histamine H4 Receptor mediates interleukin-8 and TNF-α release in human mast cells via multiple signaling pathways.
abstract: Histamine, mainly produced by mast cells, is an important inflammatory mediator in immune response. Recently Histamine H4 Receptor (H4R) was also identified in mast cells, from which pro-inflammatory cytokines and chemokines are released. However, the mechanism of how H4R mediates these cytokines and chemokines release in mast cells was still unclear. To further explore the role of H4R in the immune inflammatory response in mast cells, we tested the release of inflammatory cytokine tumor necrosis factor-α (TNF-α), chemokine interleukin-8 (IL-8) and the relevant signaling pathways activated by H4R on LAD2 cells (a human mast cell line). We found that the release of IL-8 and TNF-α were blocked by inhibitors of PI3K, ERK and Ca2+-Calcineurin-NFAT signaling pathways, while the release of these cytokines and chemokines were enhanced by the inhibitor of P38 signaling pathway. However, inhibitors of the JNK and NF-κB signaling pathways had little effect on the expression of the pro-inflammatory mediators. Moreover, activation of the H4R could induce phosphorylation of ERK, p38 and AKT in mast cells. In conclusion, we found that H4R mediates the release of inflammatory cytokine TNF-α and chemokine IL-8 in human mast cells via PI3K, Ca2+-Calcineurin-NFAT and MAPKs signaling pathways.
authors.affiliation: Shenzhen Peking University Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute Shenzhen China.
authors.forename: X-F
authors.initials: XF
authors.lastname: Chen
authors.affiliation: Peking University Shenzhen Hospital Department of Dermatology Shenzhen China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Peking University Shenzhen Hospital Department of Dermatology Shenzhen China.
authors.forename: X
authors.initials: X
authors.lastname: Dou
authors.affiliation: Peking University Shenzhen Hospital Department of Dermatology Shenzhen China.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Shenzhen Peking University Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute Shenzhen China zhangweispace@yeah.net.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Shenzhen University School of Medicine Shenzhen China echoyyyu@gmail.com.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Yu
authors.affiliation: Peking University Shenzhen Hospital Department of Dermatology Shenzhen China yubomd@hotmail.com.
authors.forename: B
authors.initials: B
authors.lastname: Yu
authors.affiliation: Shenzhen Peking University Shenzhen Key Laboratory for Translational Medicine of Dermatology, Biomedical Research Institute Shenzhen China yubomd@hotmail.com.
authors.forename: B
authors.initials: B
authors.lastname: Yu
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006632:Histamine / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008407:Mast Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; C418607:HRH4 protein, human; D016209:Interleukin-8; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium