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.

The H1 histamine receptor regulates allergic lung responses

“…Histamine can stimulate IL-5 production from CD3-stimulated T cells (38) and increase airway mucus secretion (39) via H2R. Additionally, H2R has been shown to promote Th2 responses by influencing dendritic cell activity (19) and regulating T cell proliferative responses (40). Increased expression of H2R has been found in the nasal mucosa of patients with allergic rhinitis (41).…”

“…Histamine has been reported to inhibit IL-12, IL-2, and IFN-γ production by cultured cells (14), while, conversely, IL-4, IL-5, IL-10, and IL-13 are upregulated (15)(16)(17)(18). Enhancement of Th2 responses by histamine in culture is likely the result of its effects on dendritic cells (19). Caron et al (20) found that polarization of T cell responses by histamine could be accounted for by an H2R-driven differentiation of immature dendritic cells toward a Th2-generating DC2 dendritic cell phenotype.…”

Histamine in Allergic Inflammation and Immune Modulation

“…In the differentiation process of DC1 from monocytes, HR1 and HR3 act as positive stimulants that increase antigen presentation capacity, proinflammatory cytokine production and Th1 priming activity. In contrast, HR2 acts as a suppressive molecule for antigen presentation capacity, enhances IL-10 production and induces IL-10-producing T cells or Th2 cells [45,46,47]. …”

“…Maturation of DCs results in loss of these responses. However, in maturing DCs, histamine dose-dependently enhances intracellular cAMP levels and stimulates IL-10 secretion, while inhibiting production of IL-12 via HR2 [46]. Interestingly, although human monocyte-derived DCs have both HR1 and HR2 and can induce CD86 expression by histamine, human epidermal Langerhans cells do not express either HR1 or HR2 [52].…”

“…Histamine interferes with the peripheral tolerance induced during specific immunotherapy in several pathways. Histamine induces the production of IL-10 by DCs [46]. In addition, histamine induces IL-10 production by Th2 cells [55].…”