Histamine Is a Potent Inducer of IL-18 and IFN-γ in Human Peripheral Blood Mononuclear Cells

Abstract

Histamine (10−7 to 10−4 M) concentration-dependently stimulated the production of IL-18 and IFN-γ and inhibited the production of IL-2 and IL-10 in human PBMCs. Histamine in the same concentration range did not induce the production of IL-12 at all. The stimulatory or inhibitory effects of histamine on cytokine production were all antagonized by H2 receptor antagonists ranitidine and famotidine in a concentration-dependent manner, but not by H1 and H3 receptor antagonists. Selective H2 receptor agonists, 4-methylhistamine and dimaprit, mimicked the effects of histamine on five kinds of cytokine production. The EC50 values of histamine, 4-methylhistamine, and dimaprit for the production of IL-18 were 1.5, 1.0, and 3.8 μM, respectively. These findings indicated that histamine caused cytokine responses through the stimulation of H2 receptors. All effects of histamine on cytokine responses were also abolished by the presence of either anti-IL-18 Ab or IL-1β-converting enzyme/caspase-1 inhibitor, indicating that the histamine action is dependent on mature IL-18 secretion and that IL-18 production is located upstream of the cytokine cascade activated by histamine. The addition of recombinant human IL-18 to the culture concentration-dependently stimulated IL-12 and IFN-γ production and inhibited the IL-2 and IL-10 production. IFN-γ production induced by IL-18 was inhibited by anti-IL-12 Ab, showing the marked contrast of the effect of histamine. Thus histamine is a very important modulator of Th1 cytokine production in PBMCs and is quite unique in triggering IL-18-initiating cytokine cascade without inducing IL-12 production.

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

“…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). In agreement with this study, we report no detectable effect of histamine on IL-10 production by DC.…”

“…The findings that histamine induces MCP-1 production and does not affect IL-12 production suggest that histamine may contribute to maintain a Th2 polarization in allergic diseases. However, since histamine also induces IL-18 and IFN-␥ production by PBMC (18), whether histamine may modulate Th1/Th2 orientation remains to be evaluated. Nevertheless, the observation that histamine activates DC, added to data from others showing that histamine acts on B and T cells to increase Ag receptor-mediated responses (41), suggest a direct role for histamine in the development of a specific immune response.…”

An Essential Role for IL-18 in CD8 T Cell-Mediated Suppression of IgE Responses

“…In vivo, the administration or overexpression of IL-18 resulted in increased levels of Th2 cytokines and IgE Abs, and can potently induce allergic sensitization (25,(35)(36)(37)(38). Furthermore, histamine was also reported to stimulate IL-18 production without induction of IL-12 (39).…”

Bystander suppression of allergic airway inflammation by lung resident memory CD8+ T cells

“…5 responded to these stimuli in a comparable manner to the influenza-induced effector memory CD8ϩ T cells (data not shown). IL-18 is produced by a variety of cell types in response to LPS (21), Fas ligand stimulation (22), or histamine (23). Furthermore, human macrophages have been shown to secrete IL-18 when infected in vitro with influenza A (24,25).…”