Histamine H4 receptor agonists have more activities than H4 agonism in antigen-specific human T-cell responses.

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Sugata Y, Okano M, Fujiwara T, Matsumoto R, Hattori H, Yamamoto M, Nishibori M, Nishizaki K

Histamine H4 receptor agonists have more activities than H4 agonism in antigen-specific human T-cell responses.

Immunology. 2007 Jun;121(2):266-75. Epub 2007 Mar 7.

PubMed ID

17346280 [ View in PubMed

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Abstract

Histamine not only mediates immediate allergic reactions, it also regulates cellular immune responses. H4R is the most recently identified histamine receptor (HR). In the present study, we examined the in vitro effect of histamine and H4R agonists on the responses of human T cells to purified protein derivative from Mycobacterium tuberculosis (PPD) and to Cry j1, the major allergen of Cryptomeria japonica pollen. Dimaprit, clobenpropit and clozapine, which are H4R agonists, dose-dependently blocked both PPD-induced interferon-gamma and Cry j1-induced interleukin-5 production by both peripheral blood mononuclear cells (PBMCs) and antigen-specific T-cell lines. However, the addition of thioperamide, an H3R/H4R antagonist, as well as a mixture of d-chlropheniramine, famotidine and thioperamide, did not reverse the inhibition. Pretreatment of PBMCs with SQ22536 and 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer, had varying abilities to reverse the inhibitory effects of H4R agonists, except for clobenpropit. Moreover, the addition of H4R agonists induced annexin-V expression on PBMCs, especially in CD19(+) and CD4(+) cells. cDNA microarray analysis revealed that, among 16,600 genes tested, increased expression following treatment with clozapine was seen in 0 x 8% of the genes, whereas decreased expression was seen in 3 x 0% of the genes. These results suggest that H4R agonists inhibit antigen-specific human T-cell responses, although H4R does not appear to be important for this effect. In addition, the present study indicated that there may be orphan receptors or HR subtypes which can bind dimaprit, clobenpropit and clozapine, and that can exert an inhibitory effect on antigen-specific cellular responses via a cAMP/cAMP-dependent protein kinase-dependent, apoptotic pathway.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Clozapine	Histamine H4 receptor	Protein	Humans	No	Antagonist	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Clozapine	Approved	ABCG1	9619	upregulated	Clozapine results in increased expression of ABCG1 mRNA	21q22.3
Clozapine	Approved	ABLIM2	84448	upregulated	Clozapine results in increased expression of ABLIM2 mRNA	4p16.1
Clozapine	Approved	CCL1	6346	downregulated	Clozapine results in decreased expression of CCL1 mRNA	17q12
Clozapine	Approved	CXCL1	2919	downregulated	Clozapine results in decreased expression of CXCL1 mRNA	4q13.3
Clozapine	Approved	CXCL5	6374	downregulated	Clozapine results in decreased expression of CXCL5 mRNA	4q13.3
Clozapine	Approved	FGFBP2	83888	upregulated	Clozapine results in increased expression of FGFBP2 mRNA	4p15.32
Clozapine	Approved	IFNG	3458	downregulated	Clozapine results in decreased expression of IFNG mRNA	12q15
Clozapine	Approved	LEAP2	116842	upregulated	Clozapine results in increased expression of LEAP2 mRNA	5q31.1
Clozapine	Approved	MBP	4155	upregulated	Clozapine results in increased expression of MBP mRNA	18q23
Clozapine	Approved	MC1R	4157	upregulated	Clozapine results in increased expression of MC1R mRNA	16q24.3
Clozapine	Approved	MMP10	4319	downregulated	Clozapine results in decreased expression of MMP10 mRNA	11q22.2
Clozapine	Approved	MMP7	4316	downregulated	Clozapine results in decreased expression of MMP7 mRNA	11q22.2
Clozapine	Approved	OVGP1	5016	upregulated	Clozapine results in increased expression of OVGP1 mRNA	1p13.2
Clozapine	Approved	SPP1	6696	downregulated	Clozapine results in decreased expression of SPP1 mRNA	4q22.1
Clozapine	Approved	TNFSF15	9966	downregulated	Clozapine results in decreased expression of TNFSF15 mRNA	9q32