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

作者：Masuda Kazuya; Kimura Akihiro; Hanieh Hamza; Nam Trung Nguyen; Nakahama Taisuke; Chinen Ichino; Otoyo Yuichi; Murotani Tomotaka; Yamatodani Atsushi; Kishimoto Tadamitsu^*

来源：International Immunology, 2011, 23(10): 637-645.

DOI：10.1093/intimm/dxr072

• aryl hydrocarbon receptor
• histamine
• histidine decarboxylase
• lipopolysaccharide
• Sp1

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-kappa B 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.

• 出版日期2011-10