Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization

Abstract

Atopic diseases such as allergy and asthma are characterized by increases in Th2 cells and serum IgE antibodies. The binding of allergens to IgE on mast cells triggers the release of several mediators, of which histamine is the most prevalent. Here we show that histamine, together with a maturation signal, acts directly upon immature dendritic cells (iDCs), profoundly altering their T cell polarizing capacity. We demonstrate that iDCs express two active histamine receptors, H1 and H2. Histamine did not significantly affect the LPS-driven maturation of iDCs with regard to phenotypic changes or capacity to prime naive T cells, but it dramatically altered the repertoire of cytokines and chemokines secreted by mature DCs. In particular, histamine, acting upon the H2 receptor for a short period of time, increased IL-10 production and reduced IL-12 secretion. As a result, histamine-matured DCs polarized naive CD4 + T cells toward a Th2 phenotype, as compared with DCs that had matured in the absence of histamine. We propose that the Th2 cells favor IgE production, leading to increased histamine secretion by mast cells, thus creating a positive feedback loop that could contribute to the severity of atopic diseases.

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).…”

“…Previous studies were controversial at this point; Idzko et al (12) found a suppression of IL-12p70 production by R-␣-MeH, whereas Mazzoni et al (13) and Caron et al (10) were unable to reduce histamine-induced IL-12p70 production with the H3R and (less efficient) H4R antagonist thioperamide. In our experiments, histamine-induced IL12p70 suppression was rescued by thioperamide pretreatment of MoDC (Fig.…”

“…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).…”

Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma

“…12,13 As activators of cytokine production in response to infection, TLRs may participate in early life Th1 immunophenotype development. 14,15 Genetic variation in these receptors may thus influence risk for either Th1 (infectious) or Th2 (atopic) disease. Additionally, two missense mutations of the TLR4 gene (Asp299Gly and Thr399Ile) have been associated with a decreased response to inhaled endotoxin in humans.…”