期刊
INTERNATIONAL IMMUNOLOGY
卷 23, 期 10, 页码 637-645出版社
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxr072
关键词
aryl hydrocarbon receptor; histamine; histidine decarboxylase; lipopolysaccharide; Sp1
类别
资金
- National Institute of Biomedical Innovation
- Chugai-Roche Pharmaceutical Co. Ltd, Tokyo, Japan
- Grants-in-Aid for Scientific Research [23790545] Funding Source: KAKEN
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.
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