Central injection of nitric oxide synthase inhibitors increases peripheralinterleukin-6 and serum amyloid A: involvement of adrenaline from adrenal medulla

1 Accumulating evidence suggests that plasma levels of interleukin-6 (IL-6) , a major cytokine stimulating the synthesis of acute phase proteins, are i ntimately regulated by the central nervous system (CNS). 2 In the present study, effects of intracerebroventricular (i.c.v) injectio n of N-G-nitro-L-arginine methyl ester (L-NAME) or 7-nitroindazole, nitric oxide synthase (NOS) inhibitors, on plasma IL-6 levels and peripheral IL-6 mRNA expression were examined in mice. 3 L-NAME (0.1-2 mu g per mouse i.c.v.) and 7-nitroindazole (0.2-2 mu g per mouse i.c.v.) induced a dose-dependent increase in plasma IL-6 levels and a subsequent increase in circulating serum amyloid A, a liver acute-phase pr otein. In contrast, an intraperitoneal (i.p.) injection of L-NAME up to the dose of 25 mu g per mouse had no effect. 4 Pretreatment with yohimbine (alpha(2)-adrenergic antagonist; 1 mg kg(-1) i.p.), or ICI-118,551 (beta(2)-adrenergic antagonist; 2 mg kg(-1) i.p.), bu t not with prazosin (alpha(2)-adrenergic antagonist; 1 mg kg(-1) i.p.), nor betaxolol (beta(1)-adrenergic antagonist; 2 mg kg(-1) i.p.), significantly inhibited the central L- NAME-induced plasma IL-6 levels. 5 I.c.v. (50 mu g per mouse) or i.p. (100 mg kg(-1)) pretreatment with 6-hy droxydopamine had no effect on central L-NAME-induced plasma IL-6 levels. H owever, intrathecal (i.t.) pretreatment with 6-hydroxydopamine (20 mu g per mouse) markedly inhibited central L-NAME-induced plasma IL-6 levels. Both yohimbine (1.5 mu g per mouse i.t.) and ICI-118,551 (1.5 mu g per mouse i.t .) were effective in inhibition of central L-NAME-induced plasma IL-6 level s. 6 There was an elevation of base-line plasma IL-6 levels in adrenalectomize d animals. The adrenalectomy-enhanced levels were not further increased by central L-NAME. 7 L-NAME (2 mu g per mouse i.c.v.) induced an increase in IL-6 mRNA express ion in liver, spleen, and lymph node. 8 These results suggest that NOS activity in the brain tonically down-regul ates peripheral IL-6 by inhibiting adrenaline release from the adrenal medu lla.