Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c-Rel activity.
BACKGROUND
Histamine exerts diverse effects on immune regulation through four types of histamine receptors (HRs). Among them, type 1 receptor (H1R) plays an important role in allergic inflammation. Dendritic cells (DCs), which express at least three types of HRs, are professional antigen-presenting cells controlling the development of allergic inflammation. However, the molecular mechanisms involved in H1R-mediated NF-ĸB signaling of DCs remain poorly defined.


METHODS
Bone-marrow (BM)-derived DCs (BM-DCs) were treated with H1R inverse agonists to interrupt basal H1R-mediated signaling. The crosstalk of H1R-mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay, NF-ĸB subunit analysis using Western blotting and TNF-α promoter activity using chromatin immunoprecipitation.


RESULTS
Blockage of H1R signaling by inverse agonists significantly inhibited TNF-α and IL-6 production of BM-DCs. H1R-specific agonists were able to enhance TNF-α production, but this overexpression was significantly inhibited by NF-ĸB inhibitor. The H1R inverse agonist ketotifen also suppressed cellular NF-ĸB activity, suggesting crosstalk between H1R and NF-ĸB signaling in DCs. After comprehensive analysis of NF-ĸB subunits, c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs, which led to inhibition of the promoter activity of TNF-α. Finally, adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo.


CONCLUSIONS
Our results suggest that c-Rel controls H1R-mediated proinflammatory cytokine production in DCs. This study provides a potential mechanism of H1R-mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC.
Chin-Lai
CL
Lee
Shih-Hsien
SH
Hsu
Yuh-Jyh
YJ
Jong
Chih-Hsing
CH
Hung
Jau-Ling
JL
Suen
D019264:Adoptive Transfer; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D054314:Drug Inverse Agonism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D017442:Histamine Agonists / Q000494:pharmacology; D006967:Hypersensitivity / Q000188:drug therapy / Q000276:immunology*; D007165:Immunosuppression Therapy; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007665:Ketotifen / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000235:genetics / Q000378:metabolism*; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000276:immunology; D011969:Receptors, Histamine H1 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D017442:Histamine Agonists; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D011969:Receptors, Histamine H1; D014409:Tumor Necrosis Factor-alpha; D007665:Ketotifen