IL-6 is a major cytokine that is responsible for inducing the acute-phase proteins in liver (5)⇓. The results of the present study suggest that stimulation of nicotinic receptors in the brain can induce hepatic and splenic IL-6, which may subsequently lead to the increase in the hepatic acute-phase protein synthesis and in plasma concentration of acute-phase proteins. Although the nicotine-induced increase of IL-6 mRNA expression in the liver was less marked than that in the spleen, considering the ∼12- to 13-fold greater organ weight of the liver compared with the spleen in male ICR mouse used in the present study, the contribution of liver to nicotine-induced plasma IL-6 levels may not be less, and may even be more, than that of spleen. This central nicotine-induced increase in plasma IL-6 response may be related at least in part to the increase reported in plasma concentrations of IL-6 and acute-phase proteins (such as fibrinogen and C reactive protein) associated with cigarette smoking (43⇓44⇓45⇓46⇓47⇓48)⇓. In addition, because IL-6 can affect various immunological parameters (49)⇓, the nicotine-induced IL-6 responses demonstrated in the present study may also contribute to the reported changes in immune functions induced by nicotine administration (23⇓, 50⇓51⇓52⇓53)⇓. Last, as IL-6 is very effective in stimulating ACTH secretion (54)⇓, it can be speculated that central nicotine-induced plasma levels of IL-6 may at least partly contribute to the central nicotine-induced increase in hypothalamo-pituitary-adrenal axis (18⇓, 53)⇓. In conclusion, the results of the present study suggest that stimulation of central nicotinic receptors induces plasma IL-6 levels and IL-6 mRNA expression in the liver and spleen via the peripheral sympathetic nervous system. Pharmacological evidence for the involvement of α[SUB]1[/SUB]-, α[SUB]2[/SUB]-, and β[SUB]2[/SUB]-adrenoreceptors was presented. The modulation of plasma cytokine levels by stimulation of central nicotinic receptors may add a new aspect of the complex pharmacological effects of nicotine, one of the drugs most widely used by humans.
