Histamine inhibits IL-1β release induced by LPS administration in N9 microglial cells (a) and in hippocampal organotypic slice cultures (b) measured by ELISA. (a) N9 microglial cells, upon inflammatory challenge induced by LPS (100 ng/ml), are able to release a significantly higher amount of proinflammatory cytokine IL-1β when compared to untreated cells. Histamine treatment (100 μM) significantly inhibited this effect through the activation of H4R. Accordingly, histamine-loaded microparticles (μP 10 μg/ml) mimicked the anti-inflammatory effect of histamine (left graph). The anti-inflammatory action of histamine appears to modulate specifically the IL-1β signaling pathway, since it does not alter the release of another relevant proinflammatory cytokine, such as TNF-α, in the presence of 100 ng/ml LPS. Additionally, the application of histamine-loaded microparticles (10 μg/ml) did not inhibit LPS-induced TNF-α release (right graph). (b) Regarding hippocampal organotypic slice cultures, only soluble histamine significantly decreased IL-1β release induced by LPS. Again, H4R activation also mimicked the effect of histamine, whereas H4R blockade partially recuperated LPS-induced IL-1β release (right graph). Data are expressed as mean ± SEM (n = 3-11), (*p < 0.05, **p < 0.01, ***p < 0.001, using Bonferroni’s multiple comparison test).