alpha1-Adrenergic receptor antagonists induce production of IL-18 and expression of ICAM-1 and CD40 in human monocytes.
The activation of T cells plays a role in antitumor response. Monocytes activate T cells by inducing the cell-to-cell interaction that involves the engagement of adhesion molecules with their ligands, and the production of IL-18. The authors examined the effect of the quinazoline-based alpha1-adrenergic receptor antagonists bunazosin, doxazosin, prazosin, and terazosin on the expression of adhesion molecules such as ICAM-1, B7.1, B7.2, CD40, and CD40L on monocytes isolated from human peripheral blood mononuclear cells. Doxazosin, prazosin, and terazosin induced the expression of ICAM-1 and CD40 but had no effect on the expression of B7.1, B7.2, and CD40L. Moreover, IL-18 was detected in the medium of incubated monocytes treated with doxazosin, prazosin, and terazosin. Bunazosin did not affect adhesion molecule expression and IL-18 production, suggesting that the chemical structure of quinazoline might not be related to the effect of doxazosin, prazosin, and terazosin. Although caspase-1 inhibitor completely abolished the production of IL-18, anti-IL-18 mAb and caspase-1 inhibitor partially inhibited the increase in ICAM-1 and CD40 expression induced by doxazosin, prazosin, and terazosin. Doxazosin, prazosin, and terazosin can induce monocyte activation with a specific pattern of expression of adhesion molecules and IL-18 production, and this may lead to T-cell activation through the cell-to-cell interaction. The activation of T cells induced by the increase of the expression of ICAM-1 and CD40 and the production of IL-18 may be involved in the anti-cancer effects of doxazosin, prazosin, and terazosin.
Takahashi
Hideo Kohka
HK
Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Iwagaki
Hiromi
H
Tamura
Ryuji
R
Katsuno
Goutarou
G
Xue
Dong
D
Sugita
Sachi
S
Mori
Shuji
S
Yoshino
Tadashi
T
Tanaka
Noriaki
N
Nishibori
Masahiro
M
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017292:Doxazosin / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D011224:Prazosin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000031:analogs & derivatives* / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D020382:Interleukin-18; D008562:Membrane Glycoproteins; D011799:Quinazolines; D015842:Serine Proteinase Inhibitors; C425776:tyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D014108:Tosylphenylalanyl Chloromethyl Ketone; C041226:Terazosin; C018176:bunazosin; D017292:Doxazosin; D011224:Prazosin