Epinastine hydrochloride antagonism against interleukin-4-mediated T cell cytokine imbalance in vitro.
BACKGROUND
Interleukin (IL)-4 is well accepted to be a cytokine that plays many roles in the regulation of immune responses. Although the primary pharmacological target of antihistamines has been regarded as the histamine H1 receptor, there is little information about the influence of antihistamines on IL-4-mediated immune responses. The present study was undertaken to examine whether H1 receptor antagonists could modulate IL-4-mediated immune responses in vitro.


METHODS
CD4+ T cells from normal human peripheral blood (1 x 10(6) cells/ml) were incubated with various concentrations of epinastine hydrochloride (EP) or chlorpheniramine (CH) for 30 min and then stimulated with 10.0 ng/ml IL-4. After 24 h, culture supernatants were collected and assayed for IL-5, IL-6, IL-13 and interferon-gamma by ELISA. The influence of EP on transcription factor activation and mRNA expression for cytokines was also examined.


RESULTS
Addition of EP into cell cultures at more than 20.0 ng/ml significantly suppressed the production of IL-5, IL-6 and IL-13, which were increased by IL-4 stimulation. EP at more than 20.0 ng/ml also suppresses nuclear factor-kappaB activation, signal transducers and activators of transcription 6 phosphorylation and mRNA expression, which were upregulated by IL-4 stimulation. However, the ability of CD4+ T cells to produce interferon-gamma was decreased by IL-4 stimulation, which was dramatically restored by treatment with EP at more than 15.0 ng/ml. On the other hand, CH, a first-generation H1 receptor antagonist, could not inhibit cytokine production from CD4+ T cells in response to IL-4 stimulation, even when 90.0 ng/ml of the agent was added to cell cultures.


CONCLUSIONS
The present results strongly suggest that EP, a second-generation H1 receptor antagonist, interferes with IL-4-activated signaling in CD4+ T cells and results in favorable modification of the allergic disease state or conditions.
Kanai
Ken-ichi
K
Department of Otolaryngology, School of Medicine, Showa University, Tokyo, Japan.
Asano
Kazuhito
K
Watanabe
So
S
Kyo
Yoshiyuki
Y
Suzaki
Harumi
H
D000328:Adult; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002744:Chlorpheniramine / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D018926:Anti-Allergic Agents; D016207:Cytokines; D003984:Dibenzazepines; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D012333:RNA, Messenger; D015847:Interleukin-4; D002744:Chlorpheniramine; C053090:epinastine