title: Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages.
abstract: Macrophages play a pivotal role in innate immune responses to pathogens via toll-like receptors. We previously demonstrated that aryl hydrocarbon receptor (Ahr) in combination with signal transducer and activator of transcription 1 (Stat1) negatively regulates pro-inflammatory cytokine production by inhibiting nuclear factor-κB activation in macrophages after LPS stimulation. Here, we show that Ahr also negatively regulates production of the pro-inflammatory cytokine IL-6 by suppressing histamine production in macrophages stimulated by LPS. We found that Ahr-Sp1 complex, independent of Stat1, represses histidine decarboxylase expression by inhibiting LPS-induced Sp1 phosphorylation on Ser residues in macrophages; this leads to suppression of histamine production. Moreover, we found that loratadine and chlorpromazine, histamine 1 receptor (H1R) antagonists, more effectively impair the production of LPS-induced IL-6 than that of other inflammatory cytokines in Ahr(-/-) macrophages. Collectively, these results demonstrate that Ahr negatively regulates IL-6 production via H1R signaling through the suppression of histamine production in macrophages following LPS stimulation.
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Masuda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kimura
authors.forename: Hamza
authors.initials: H
authors.lastname: Hanieh
authors.forename: Nam Trung
authors.initials: NT
authors.lastname: Nguyen
authors.forename: Taisuke
authors.initials: T
authors.lastname: Nakahama
authors.forename: Ichino
authors.initials: I
authors.lastname: Chinen
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Otoyo
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Murotani
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamatodani
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D006632:Histamine / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D006632:Histamine; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018336:Receptors, Aryl Hydrocarbon; D011969:Receptors, Histamine H1; D016329:Sp1 Transcription Factor; C484722:Ahr protein, mouse