Histamine Promotes the Release of IL‐6 in Nasal Fibroblasts

Abstract

Objectives: Based on the close relationship between histamine and IL-6, we hypothesized that histamine plays a role in the production of cytokines such as IL-6 and is involved in the microenvironmental controls of the allergic inflammatory process. We describe in nasal fibroblasts the effect of histamine on the production of IL-6, the major histamine receptors, and the related underlying mechanisms. Methods: Nasal fibroblasts from eight normal patients were incubated. Reverse transcriptase polymerase chain reaction was performed for histamine receptors (H1R, H2R, H3R, and H4R) to identify which histamine receptor is expressed in nasal fibroblasts. The fibroblasts were treated with histamine with or without a histamine-receptor antagonist, and IL-6 production was measured using ELISA. Three MAP kinases (p38, ERK, and JNK) and NF-κB were evaluated as downstream signaling molecules by Western blot analysis and Luciferase reporter assay. Results: Expression levels of all histamine receptors were elevated. The level of IL-6 protein expression increased significantly with histamine stimulation. Among the histamine-receptor specific antagonists, only H1R antagonist significantly decreased IL-6 production in histamine-stimulated nasal fibroblasts. Histamine increased the level of phosphorylated p38 (pp38), pERK, pJNK expression, and NF-κB induction. H1R antagonist reversed the increased expression of pp38 and NF-κB in histamine-induced nasal fibroblasts, but not pERK and pJNK. p38 inhibitor markedly suppressed the increased production of IL-6 in histamine-stimulated nasal fibroblasts. Conclusions: The results of the present study suggest that antihistamines could be involved in the regulation of cytokines such as IL-6, beyond the blockage of the histamine effect as an inflammatory mediator in nasal fibroblasts.