Effect of nicotine on advanced glycation end product-induced immune response in human monocytes

The up-regulation of adhesion molecule expressions on monocytes enhances cell-to-cell interactions with T cells, leading to cytokine production. Advanced glycation end products (AGEs) are modifications of proteins/lipids that become nonenzymatically glycated after contact with aldose sugars. Among various subtypes of AGEs, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) induce the expressions of intercellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes, the production of interferon-γ and tumor necrosis factor-α, and the lymphocyte proliferation in human peripheral blood mononuclear cells. Nicotine is reported to inhibit the activation of monocytes via nicotinic acetylcholine receptor α7 subunit (α7-nAChR). In the present study, we found that nicotine inhibited the actions of AGE-2 and AGE-3. A nonselective and selective α7-nAChR antagonist, mecamylamine and α-bungarotoxin, reversed the inhibitory effects of nicotine, suggesting the involvement of α7-nAChR stimulation. Nicotine induced the expression of cyclooxygenase-2, prostaglandin E₂ (PGE₂), and cAMP in the presence and absence of AGE-2 and AGE-3. PGE₂ is known to activate the EP₂/EP₄ receptor, increasing the cAMP level and protein kinase A (PKA) activity. The actions of nicotine were reversed in part by an EP₂-receptor antagonist, AH6809, an EP₄-receptor antagonist, AH23848, and a PKA inhibitor, N-[2-(pbromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H89). These results indicate that the mechanism of action of nicotine may be partially via endogenous PGE₂ production.