The immunosuppressive effects of nicotine during human mixed lymphocyte reaction.
Cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 on monocytes and their ligands on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1, B7.1, B7.2 and CD40, production of interferon (IFN)-gamma and IL-12 and proliferation of lymphocytes during human mixed lymphocyte reaction. Nicotine is known to inhibit the production of pro-inflammatory cytokines from macrophages through the stimulation of nicotinic acetylcholine receptor alpha7 subunit. In the present study, we examined the effect of increasing concentrations ranging from 0.1 to 100 microM of nicotine on the expression of ICAM-1, B7.1, B7.2 and CD40, production of IFN-gamma and IL-12 and proliferation of lymphocytes during mixed lymphocyte reaction treated with IL-18 at 100 ng/ml for 48 h. Nicotine inhibited the expression of adhesion molecules, cytokine production and lymphocyte proliferation. The IC50 values of nicotine for inhibition of the IL-18-enhanced ICAM-1 expression, IFN-gamma production and proliferation were 1, 1 and 2 microM, respectively. A non-selective and a selective antagonist for nicotinic acetylcholine receptor alpha7 subunit, mecamylamine and alpha-bungarotoxin abolished the effects of nicotine. The actions of nicotine might depend on stimulation of nicotinic acetylcholine receptor alpha7 subunit. Nicotine induced prostaglandin E(2) production during mixed lymphocyte reaction. The inhibitors of cyclooxygenase (COX)-2 and protein kinase A (PKA) at 100 microM inhibited the actions of nicotine, suggesting that the endogenous prostaglandin E(2) might be, at least, partially involved the actions of nicotine.
Takahashi
Hideo K
HK
Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Iwagaki
Hiromi
H
Hamano
Ryosuke
R
Kanke
Toru
T
Liu
Keyue
K
Sadamori
Hiroshi
H
Yagi
Takahito
T
Yoshino
Tadashi
T
Tanaka
Noriaki
N
Nishibori
Masahiro
M
D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents; D020382:Interleukin-18 / Q000494:pharmacology; D007959:Lymphocyte Culture Test, Mixed; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D015815:Cell Adhesion Molecules; C579167:Chrna7 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D007166:Immunosuppressive Agents; D020382:Interleukin-18; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone