Effect of histamine H1 receptor antagonists on TARC/CCL17 and MDC/CCL22 production from CD14+ cells induced by antigenic stimulation in vitro.
BACKGROUND
Thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) are accepted to be important molecules in the development and maintenance of allergic diseases. Although several types of histamine H(1) receptor antagonist (antihistamine) have been developed and used for the treatment of allergic diseases, the influence of antihistamines on TARC and MDC production is not well understood.


OBJECTIVE
The present study was undertaken to examine the influence of antihistamines on TARC and MDC production from CD14+ cells after antigenic stimulation in vitro.


METHODS
CD14+ cells prepared from patients with pollinosis to Japanese cedar pollen were stimulated with specific allergen extracted from Japanese cedar pollen (Cry j 1) in the presence of azelastine (AZE), ketotifen (KET), fexofenadine (FEX) and oxatomide (OXA) for 6 days. TARC and MDC levels in culture supernatants were examined by ELISA. We also examined the influence of FEX on TARC and MDC mRNA expression, phosphorylation of mitogen-activated protein kinases (MAPKs) and transcription factor activation in CD14+ cells after Cry j 1 stimulation.


RESULTS
FEX at 250 ng/ml, which is almost equal to therapeutic blood levels, caused a significant inhibition of TARC and MDC production.However, AZE, OXA and KET required higher concentrations than their therapeutic blood levels to suppress production of these factors. FEX at 250 ng/ml also suppressed NF-κB activation, phosphorylation of p38 MAPK and extracellular signal-regulated kinases 1 and 2 and expression of mRNA for TARC and MDC.


CONCLUSIONS
These results suggest that antihistamines, especially FEX, suppress CC chemokine production from CD14+ cells through interference with antigen-mediated signaling and result in favorable modification of allergic disease states or conditions.
Department of Otolaryngology, School of Medicine, Showa University, Tokyo, Japan.
Naruo
N
Shoji
Kazuhito
K
Asano
Atsuko
A
Furuta
Kojiro
K
Hirano
Harumi
H
Suzaki
D000328:Adult; D052179:Antigens, Plant / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D054414:Chemokine CCL17 / Q000235:genetics / Q000378:metabolism*; D054422:Chemokine CCL22 / Q000235:genetics / Q000378:metabolism*; D002744:Chlorpheniramine / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050982:GATA1 Transcription Factor / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007665:Ketotifen / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010940:Plant Proteins / Q000276:immunology; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016593:Terfenadine / Q000031:analogs & derivatives / Q000494:pharmacology; D014373:Tuberculin / Q000276:immunology; D055815:Young Adult
D052179:Antigens, Plant; C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; C065290:Cry j I protein, Cryptomeria japonica; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D006634:Histamine H1 Antagonists; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D010793:Phthalazines; D010879:Piperazines; D010940:Plant Proteins; D014373:Tuberculin; D002744:Chlorpheniramine; D016593:Terfenadine; D006632:Histamine; C093230:fexofenadine; D048049:Extracellular Signal-Regulated MAP Kinases; C015408:oxatomide; D007665:Ketotifen; C020976:azelastine