Histamine Polarizes Human Dendritic Cells into Th2 Cell-Promoting Effector Dendritic Cells

Abstract

Allergic disorders are characterized by allergen-specific Th2-biased responses. Signals controlling Th2 cell polarization, especially those acting by polarizing dendritic cells (DC) into Th2-promoting DC (DC2), are not well known. Histamine, a mediator released by allergen-stimulated mast cells from allergic subjects, has been reported to activate human immature DC. We have therefore tested whether histamine affects DC polarization. We report here that histamine inhibits LPS-induced IL-12 production and polarizes uncommitted maturing DC into effector DC2. DC matured in the presence of histamine fail to produce IL-12 upon subsequent stimulation and prime Th2 responses, even in presence of IFN-γ, a potent DC1-driving factor. All these effects are mediated through both H1 and H2 receptors. These data show that histamine is a potent DC2-polarizing factor and provide evidence for a novel mechanism that explains the initiation and maintenance of a predominant Th2 response in allergic disorders.

Histamine H4 Receptor Stimulation Suppresses IL-12p70 Production and Mediates Chemotaxis in Human Monocyte-Derived Dendritic Cells

“…IL-12p70 suppression via the H2R observed in our study is in agreement with previous studies (10,12,13). The ability of the G␣ s -coupled H2R to induce cAMP in monocytes and MoDC has been described previously (11,12,35,36).…”

“…Comparing monocytes and MoDC, MoDC appear to express higher levels of H4R mRNA also in another study (22). Studies investigating H3R mRNA expression in MoDC are controversial; some detected mRNA signal (12, 13), whereas others found only a faint (22) or no signal (10). This might be due to the down-regulation of H3R mRNA during the differentiation from monocytes to MoDC observed by us and can be explained by different culture conditions.…”

“…The expression of H1R and H2R on human monocyte-derived DC (MoDC) has also recently been reported (10 -13), and stimulation of MoDC with histamine resulted in induction of CD86 surface expression (14), suppression of IL-12 production (10 -13), and polarization of DC into Th2 cell promoting cells (10,13).…”

“…Whereas some studies were able to detect the receptor mRNA by RT-PCR (12,13), others found only a faint (22) or no signal (10). Functional analyses in these studies were also controversial, describing no effect of the H3R antagonist thioperamide on histamine-induced IL-12p70 suppression (10,13) or suppression of IL-12p70 by the H3R agonist R-␣-methylhistamine (R-␣-MeH) (12). However, the compounds that were used to address the H3R also bind to the H4R and, therefore, do not allow the discrimination of the two receptors (6).…”

Prostaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T cell response

“…In addition to the genetic background, it is likely that the tissue environment also determines the capacity of DC to induce Th2 responses consecutively to allergen exposure. For instance, among the main mediators released early during the allergic reaction, histamine and PGD 2 are important for DC functions [8][9][10][11].…”