Importance of histamine in the cytokine network in the lung through H-2 and H-3 receptors: Stimulation of IL-10 production

Histamine, a well-known inflammatory mediator, has been implicated in vario us immunoregulatory effects that are poorly understood. Thus, we tested the hypothesis that histamine inhibits the release of a proinflammatory cytoki ne, namely TNF, by stimulating the release dan anti-inflammatory cytokine, IL-IO. Alveolar macrophages (AMs) from humans, Sprague Dawley rats,. and th e AM cell line, NR8383, were treated with different concentrations of hista mine (10(-5)-10(-7) M) for 2 h prior to their stimulation with suboptimal c oncentration of LPS (1 ng/ml) for 4 h, Histamine inhibited TNF release in a dose-dependent manner. This inhibition was mimicked by H-2 and H-3 recepto r agonists, but not by H-1 receptor agonist. Furthermore, we demonstrated t he expression of H-3 receptor mRNA in human AMs, Interestingly, treatment o f AMs with anti-IL-10, anti-PGE(2), or a NO synthase inhibitor (N-omega-nit ro-L-arginine methyl ester) before the addition of histamine abrogated the inhibitory effect of the latter on TNF release. Histamine treatment (10(-5) M) increased the release of IL-10 from unstimulated (2,2-fold) and LPS-sti mulated (1.7-fold) AMs, Unstimulated AMs, NR8383, express few copies of IL- 10 mRNA, as tested by quantitative PCR, but, expression of IL-10 was increa sed by 1.5-fold with histamine treatment. Moreover, the stimulation of IL-1 0 release by histamine was abrogated by pretreatment with anti-PGE(2) or th e NO synthase inhibitor, N omega-nitro-L-arginine methyl ester, Thus, hista mine increases the synthesis and release of IL-10 from AMs through PGE(2) a nd NO production. These results suggest that histamine may play an importan t role in the modulation of the cytokine network.