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The immunosuppressive effects of nicotine during human mixed lymphocyte reaction
Hideo K Takahashi1, Hiromi Iwagaki, Ryosuke Hamano
1Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
Insights
Nicotine inhibits interleukin-18-induced immune responses, including adhesion molecule expression, cytokine production, and lymphocyte proliferation, via the nicotinic acetylcholine receptor alpha7 subunit. These effects involve prostaglandin E2 and cyclooxygenase-2 pathways.
Area of Science:
- Immunology
- Pharmacology
Background:
- Cell-to-cell interactions via molecules like ICAM-1 and B7 on monocytes and T-cells are crucial for immune responses.
- Interleukin-18 (IL-18) elevates during organ transplant rejection and promotes immune cell activation, including ICAM-1 expression and lymphocyte proliferation.
- Nicotine's known anti-inflammatory effects on macrophages involve the nicotinic acetylcholine receptor alpha7 subunit.
Purpose of the Study:
- To investigate nicotine's impact on IL-18-stimulated immune cell interactions.
- To determine nicotine's effect on adhesion molecule expression, cytokine production (IFN-gamma, IL-12), and lymphocyte proliferation in mixed lymphocyte reactions.
- To elucidate the role of the nicotinic acetylcholine receptor alpha7 subunit and prostaglandin E2 in nicotine's immunomodulatory actions.
Main Methods:
- Mixed lymphocyte reactions were treated with IL-18 and varying concentrations of nicotine (0.1–100 microM).
- Expression of ICAM-1, B7.1, B7.2, and CD40, along with IFN-gamma and IL-12 production, were measured.
- Lymphocyte proliferation was assessed, and the effects of nicotine antagonists (mecamylamine, alpha-bungarotoxin), COX-2, and PKA inhibitors were evaluated.
Main Results:
- Nicotine significantly inhibited IL-18-induced ICAM-1 expression, IFN-gamma and IL-12 production, and lymphocyte proliferation.
- The inhibitory effects of nicotine were blocked by antagonists of the nicotinic acetylcholine receptor alpha7 subunit.
- Nicotine stimulated prostaglandin E2 production, and its actions were partially inhibited by COX-2 and PKA inhibitors.
Conclusions:
- Nicotine exerts immunosuppressive effects on IL-18-mediated immune responses.
- The nicotinic acetylcholine receptor alpha7 subunit and prostaglandin E2 signaling pathways are implicated in nicotine's immunomodulatory actions.
- These findings suggest potential therapeutic roles for nicotine or its derivatives in managing immune-related conditions like transplant rejection.
Abstract:
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.
