Importance of histamine in the cytokine network in the lung through H2 and H3 receptors:: Stimulation of IL-10 production

Histamine, a well-known inflammatory mediator, has been implicated in various immunoregulatory effects that are poorly understood. Thus, we tested the hypothesis that histamine inhibits the release of a proinflammatory cytokine, namely TNF, by stimulating the release dan anti-inflammatory cytokine, IL-IO. Alveolar macrophages (AMs) from humans, Sprague Dawley rats,. and the AM cell line, NR8383, were treated with different concentrations of histamine (10(-5)-10(-7) M) for 2 h prior to their stimulation with suboptimal concentration 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 receptor agonists, but not by H-1 receptor agonist. Furthermore, we demonstrated the expression of H-3 receptor mRNA in human AMs, Interestingly, treatment of AMs with anti-IL-10, anti-PGE(2), or a NO synthase inhibitor (N-omega-nitro-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-stimulated (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 increased by 1.5-fold with histamine treatment. Moreover, the stimulation of IL-10 release by histamine was abrogated by pretreatment with anti-PGE(2) or the NO synthase inhibitor, N omega-nitro-L-arginine methyl ester, Thus, histamine increases the synthesis and release of IL-10 from AMs through PGE(2) and NO production. These results suggest that histamine may play an important role in the modulation of the cytokine network.