The stimulation of TH2 cells results in increased IL-5 and IL-13 production via the H4 receptor

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H-4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches. Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H-4 receptor impacts TH2 cells and contributes to AD pathophysiology. Methods: Total CD4(+) T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real-time PCR and ELISA. Results: H-4 receptor mRNA expression was upregulated concentration dependent upon IL-4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H-4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL-5 and IL-13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H-4 receptor-selective-agonist when compared to the untreated control. Conclusion: We show for the first time an H-4 receptor dependent upregulation of the pro-inflammatory cytokines IL-5 and IL-13 in human TH2 cells by histamine. This suggests that the blockade of the H-4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies.