Importance of Histamine in the Cytokine Network in the Lung Through H2 and H3 Receptors: Stimulation of IL-10 Production

Abstract

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 of an anti-inflammatory cytokine, IL-10. 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 H2 and H3 receptor agonists, but not by H1 receptor agonist. Furthermore, we demonstrated the expression of H3 receptor mRNA in human AMs. Interestingly, treatment of AMs with anti-IL-10, anti-PGE2, or a NO synthase inhibitor (Nω-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-PGE2 or the NO synthase inhibitor, Nω-nitro-l-arginine methyl ester. Thus, histamine increases the synthesis and release of IL-10 from AMs through PGE2 and NO production. These results suggest that histamine may play an important role in the modulation of the cytokine network.

Histamine Induces CD86 Expression and Chemokine Production by Human Immature Dendritic Cells

“…Moreover, in accordance with data obtained using monocytes/macrophages (18 -21), histamine does not induce TNF-␣ nor IL-12 production by DC. Histamine has been shown to induce IL-10 production by alveolar macrophages (22). In contrast, others reported that histamine alone did not induce IL-10 production by PBMC (18,21).…”

“…The anti-inflammatory effects of histamine, including inhibition of LPS-induced IL-12 and TNF-␣ production and upregulation of IL-10 production by PBMC, are mediated through H2 (19 -22); one report also involves H3 receptors in histamineinduced IL-10 production by macrophages (22). However, histamine has been shown to induce IL-6 and IL-8 production by endothelial cells through both H1 and H2 receptors (14,15).…”

Histamine Induces Exocytosis and IL-6 Production from Human Lung Macrophages Through Interaction with H1 Receptors

“…Human macrophages express all types of histamine receptors, H 1 , H 2 , and H 3 (24,25). Several studies have started to highlight the complexity of histamine's effects on cytokine network in human cells depending on the type of receptor activated.…”

“…For example, activation of IL-6 production generally occurs via H 1 receptors (54 -56), whereas inhibition of IL-1, TNF-␣, and IL-12 production by LPS-stimulated human monocytes is mediated by H 2 receptors (35,36,57). Furthermore, activation of H 2 and H 3 receptors stimulates IL-10 release from human monocytes and macrophages (11,25). These findings suggest that the local release of histamine in inflamed tissues may play a role in the modulation of the cytokine network more complex than originally thought.…”

“…Although histamine has been reported either to induce (25,34) or inhibit (35,36) cytokine synthesis in human monocytes and macrophages, there are no data on the effect of this mediator on IL-6, a major cytokine produced by human macrophages (37). In these experiments, macrophages were incubated with increasing concentrations of histamine ranging from 10 Ϫ9 to 10 Ϫ6 M for 6 h at 37°C.…”