Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages

Kazuya Masuda, Akihiro Kimura, Hamza Hanieh, Nam Trung Nguyen, Taisuke Nakahama, Ichino Chinen, Yuichi Otoyo, Tomotaka Murotani, Atsushi Yamatodani, Tadamitsu Kishimoto

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42 Citations (Scopus)

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-kB 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 1/1 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.

Original languageEnglish
Pages (from-to)637-645
Number of pages9
JournalInternational immunology
Volume23
Issue number10
DOIs
Publication statusPublished - 2011 Oct

Keywords

  • Aryl hydrocarbon receptor
  • Histamine
  • Histidine decarboxylase
  • Lipopolysaccharide
  • Sp1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Masuda, K., Kimura, A., Hanieh, H., Nguyen, N. T., Nakahama, T., Chinen, I., Otoyo, Y., Murotani, T., Yamatodani, A., & Kishimoto, T. (2011). Aryl hydrocarbon receptor negatively regulates LPS-induced IL-6 production through suppression of histamine production in macrophages. International immunology, 23(10), 637-645. https://doi.org/10.1093/intimm/dxr072