Histamine H4 receptor regulates Th2-cytokine profile through thymic stromal lymphopoietin in allergic rhinitis
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Epithelial thymic stromal lymphopoietin (TSLP) promotes Th2 inflammatory responses through induction of OX40 ligand (OX40L) on dendritic cells in allergic rhinitis (AR). Emerging evidence supports the important role of histamine H4 receptor (H4R) in allergic inflammation. This study aimed to investigate the effects of H4R in Th2-cytokine profile mediated by TSLP in AR.
Human nasal epithelial cells (HNECs) from AR patients were stimulated with histamine in the presence or absence of H4R agonist (4-methylhistamine, 4-MH) and antagonist (NJ7777120, JNJ) or H1R agonist (2-pyridylethylamine). TSLP protein was measured by Western blotting and ELISA. To further elucidate the role of H4R in the in vivo situation of experimental AR, rats were sensitized and treated with JNJ or 4-MH. TSLP and OX40 ligand (OX40L) in the nasal mucosa were assayed by Western blotting. Th2 cytokines including interleukin-4, 5 and 13 in nasal lavage fluids were detected by ELISA.
Histamine alone did not induce TSLP production by HNECs. The pre-incubation with 4-MH prior to histamine promoted TSLP expression, which was inhibited by the stimulation with JNJ prior to histamine and 4-MH. The pre-incubation with 2-pyridylethylamine before histamine stimulation had no impact on TSLP production. In AR rats, the levels of TSLP and OX40L protein were increased as well as Th2 cytokines, which was further up-regulated by 4-MH treatment, while JNJ treatment attenuated these effects.
H4R activation induced TSLP production by HNECs, which up-regulated OX40L expression in the nasal mucosa of sensitized rats. These factors promoted Th2-cytokine profile in AR.
KeywordsAllergic rhinitis Human nasal epithelial cells Thymic stromal lymphopoietin Histamine H4 receptor OX40 ligand Th2 immune response
This study was carried out in the Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, so we thank Yunliang Yao, M.D., the director of the laboratory. This study was supported by the Natural Science Foundation of Huzhou, China (no. 2015YZ02), the Public Welfare Technology Application Research Project of Zhejiang Province, China (no. 2017C37146) and the National Natural Science Foundation of China (no. 31672295).
WWW: Analyzing, acquiring and interpretation the data; YLP: revising the manuscript; HWY: repeating the detection of Th2 cytokines including IL-4 and IL-13 according to the comments of Reviewer #1; BZ: repeating the experiments in mice according to the comments of Reviewer #1; SWS: drafting the article and final approval of the version to be published. We confirm that all the listed authors have participated in the study, and have seen and approved the submitted manuscript.
This study was supported by the Natural Science Foundation of Huzhou, China (No. 2015YZ02), the Public Welfare Technology Application Research Project of Zhejiang Province, China (No.2017C37146) and the National Natural Science Foundation of China (No.31672295).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The ethics committee in which all authors worked approved this study. All participants signed the informed consent. The experimental study was approved by the Institutional Review Board of Huzhou University on Principles of Laboratory Animal Care and was performed in accordance with the German Law on Protection of Animals.
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