Advertisement

Histamine H4 receptor regulates Th2-cytokine profile through thymic stromal lymphopoietin in allergic rhinitis

  • Wei Wei Wang
  • Yong Liang Pan
  • Hong Wei Yu
  • Bo Zhang
  • Sheng Wen ShaoEmail author
Rhinology
  • 51 Downloads

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

Allergic rhinitis Human nasal epithelial cells Thymic stromal lymphopoietin Histamine H4 receptor OX40 ligand Th2 immune response 

Notes

Acknowledgements

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).

Author contributions

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.

Funding

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.

Ethical approval

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.

References

  1. 1.
    Son HL, Park HR, Park YJ et al (2015) Effect of retinoic acid in a mouse model of allergic rhinitis. Allergy Asthma Immunol Res 7:590–598CrossRefGoogle Scholar
  2. 2.
    Pichavant M, Matangkasombut P, Dekruyff RH et al (2009) Natural killer T cells regulate the development of asthma. Expert Rev Clin Immunol 5:251–260CrossRefGoogle Scholar
  3. 3.
    König B, Petersen A, Bellinghausen I et al (2007) Human dendritic cells transfected with allergen-DNA stimulate specific immunoglobulin G4 but not specific immunoglobulin E production of autologous B cells from atopic individuals in vitro. Immunology 122:239–246CrossRefGoogle Scholar
  4. 4.
    North CM, Ezendam J, Hotchkiss JA et al (2016) Developing a framework for assessing chemical respiratory sensitization: a workshop report. Regul Toxicol Pharmacol 80:295–309CrossRefGoogle Scholar
  5. 5.
    Mizoguchi I, Ohashi M, Chiba Y et al (2017) Prediction of chemical respiratory and contact sensitizers by OX40L expression in dendritic cells using a novel 3D coculture system. Front Immunol 8:929CrossRefGoogle Scholar
  6. 6.
    Kaur D, Brightling C (2012) OX40/OX40 ligand interactions in T-cell regulation and asthma. Chest 141:494–499CrossRefGoogle Scholar
  7. 7.
    Salek-Ardakani S, Song J, Halteman BS et al (2003) OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J Exp Med 198:315–324CrossRefGoogle Scholar
  8. 8.
    Boita M, Garzaro M, Raimondo L et al (2015) Eosinophilic inflammation of chronic rhinosinusitis with nasal polyps is related to OX40 ligand expression. Innate Immun 21:167–174CrossRefGoogle Scholar
  9. 9.
    Cianferoni A, Spergel J (2014) The importance of TSLP in allergic disease and its role as a potential therapeutic target. Expert Rev Clin Immunol 10:1463–1474CrossRefGoogle Scholar
  10. 10.
    Ito T, Liu YJ, Arima K (2012) Cellular and molecular mechanisms of TSLP function in human allergic disorders-TSLP programs the “Th2 code” in dendritic cells. Allergol Int 61:35–43CrossRefGoogle Scholar
  11. 11.
    Soumelis V, Reche PA, Kanzler H et al (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3:673–680CrossRefGoogle Scholar
  12. 12.
    Ito T, Wang YH, Duramad O et al (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202:1213–1223CrossRefGoogle Scholar
  13. 13.
    Murakami-Satsutani N, Ito T, Nakanishi T et al (2014) IL-33 promotes the induction and maintenance of Th2 immune responses by enhancing the function of OX40 ligant. Allergol Int 63:443–455CrossRefGoogle Scholar
  14. 14.
    Bryce PJ, Mathias CB, Harrison KL et al (2006) The H1 histamine receptor regulates allergic lung responses. J Clin Investig 116:1624–1632CrossRefGoogle Scholar
  15. 15.
    Thurmond RL, Desai PJ, Dunford PJ et al (2004) A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther 309:404–413CrossRefGoogle Scholar
  16. 16.
    Dinh QT, Cryer A, Dinh S et al (2005) Transcriptional up-regulation of histamine receptor-1 in epithelial, mucus and inflammatory cells in perennial allergic rhinitis. Clin Exp Allergy 35:1443–1448CrossRefGoogle Scholar
  17. 17.
    Dunford PJ, O’Donnell N, Riley JP et al (2006) The histamine H4 mediates allergic airway inflammation by regulating the activation of CD4+ T cells. J Immunol 176:7062–7070CrossRefGoogle Scholar
  18. 18.
    Cowden JM, Riley JP, Ma JY et al (2010) Histamine H4 receptor antagonism diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines. Respir Res 11:86CrossRefGoogle Scholar
  19. 19.
    Engelhardt H, Smits RA, Leurs R et al (2009) A new generation of anti-histamines: histamine H4 receptor antagonists on their way to the clinic. Curr Opin Drug Discov Dev 12:628–643Google Scholar
  20. 20.
    Cowden JM, Riley JP, Ma JY et al (2010) Histamine H4 receptor antagonist diminishes existing airway inflammation and dysfunction via modulation of Th2 cytokines. Respir Res 11:86CrossRefGoogle Scholar
  21. 21.
    Kiss R, Keserű GM (2012) Histamine H4 receptor ligands and their potential therapeutic applications: an update. Expert Opin Ther Pat 22:205–221CrossRefGoogle Scholar
  22. 22.
    Wang W, Xu X, Zheng M et al (2013) Lipopolysaccharides induces MUC5AC overproduction in human nasal epithelium. Eur Arch Otorhinolaryngol 270:541–547CrossRefGoogle Scholar
  23. 23.
    Kang JW, Lee YH, Kang MJ et al (2017) Synergistic mucus secretion by histamine and IL-4 through TMEM16A in airway epithelium. Am J Physiol Lung Cell Mol Physiol 313:L466–L476CrossRefGoogle Scholar
  24. 24.
    Schaper K, Rossbach K, Köther B et al (2016) Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes. Pharmacol Res 113:209–215CrossRefGoogle Scholar
  25. 25.
    Wang W, Zheng M (2011) Nuclear factor kappa B pathway down-regulates aquaporin 5 in the nasal mucosa of rats with allergic rhinitis. Eur Arch Otorhinolaryngol 268:73–81CrossRefGoogle Scholar
  26. 26.
    Wang W, Zheng M (2012) Mucin 5 subtype AC expression and upregulation in the nasal mucosa of allergic rhinitis rats. Otolaryngol Head Neck Surg 147:1012–1019CrossRefGoogle Scholar
  27. 27.
    Ahmad SF, Ansari MA, Zoheir KM et al (2015) Regulation of TNF- and NF-B activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation. Immunobiology 220:889–898CrossRefGoogle Scholar
  28. 28.
    Hui CC, Yu A, Heroux D et al (2015) Thymic stromal lymphopoietin (TSLP) secretion from human nasal epithelium is a function of TSLP genotype. Mucosal Immunol 8:993–999CrossRefGoogle Scholar
  29. 29.
    Müller T, Myrtek D, Bayer H et al (2006) Functional characterization of histamine receptor subtypes in a human bronchial epithelial cell line. Int J Mol Med 18:925–931Google Scholar
  30. 30.
    Jung SY, Shin SY, Eun YG et al (2013) Changes of histamine receptors and CC chemokines in nasal epithelial cells and fibroblasts after respiratory syncytial virus infection. Am J Rhinol Allergy 27:e17–e21CrossRefGoogle Scholar
  31. 31.
    Merves J, Chandramouleeswaran PM, Benitez AJ et al (2015) Altered esophageal histamine receptor expression in eosinophilic esophagitis (EoE): implications on disease pathogenesis. PLoS One 10:e0114831CrossRefGoogle Scholar
  32. 32.
    Terada N, Hamano N, Maesako KI et al (1999) Diesel exhaust particulates upregulate histamine receptor mRNA and increase histamine-induced IL-8 and GM-CSF production in nasal epithelial cells and endothelial cells. Clin Exp Allergy 29:52–59CrossRefGoogle Scholar
  33. 33.
    Giustizieri ML, Albanesi C, Fluhr J et al (2004) H1 histamine receptor mediates inflammatory responses in human keratinocytes. J Allergy Clin Immunol 114:1176–1182CrossRefGoogle Scholar
  34. 34.
    Matsubara M, Tamura T, Ohmori K et al (2005) Histamine H1 receptor antagonist blocks histamine-induced proinflammatory cytokine production through inhibition of Ca2+-dependent protein kinase C, Raf/MEK/ERK and IKK/I kappa B/NF-kappa B signal cascades. Biochem Pharmacol 69:433–449CrossRefGoogle Scholar
  35. 35.
    Suwa E, Yamaura K, Sato S et al (2014) Increased expression of the histamine H4 receptor following differentiation and mediation of the H4 receptor on interleukin-8 mRNA expression in HaCaT keratinocytes. Exp Dermatol 23:138–140CrossRefGoogle Scholar
  36. 36.
    Ling P, Ngo K, Nguyen S et al (2004) Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol 142:161–171CrossRefGoogle Scholar
  37. 37.
    Yamauchi M, Moriyama M, Hayashida JN et al (2017) Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus. PLoS One 12:e0173017CrossRefGoogle Scholar
  38. 38.
    Pilette C, Jacobson MR, Ratajczak C et al (2013) Aberrant dendritic cell function conditions Th2-cell polarization in allergic rhinitis. Allergy 68:312–321CrossRefGoogle Scholar
  39. 39.
    Melum GR, Farkas L, Scheel C et al (2014) A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa. J Allergy Clin Immunol 134:613–621CrossRefGoogle Scholar
  40. 40.
    Shi Z, Jiang W, Wang M et al (2017) Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis. Mol Cell Biochem 430:161–169CrossRefGoogle Scholar
  41. 41.
    Kirmaz C, Bayrak P, Yilmaz O et al (2005) Effects of glucan treatment on the Th1/Th2 balance in patients with allergic rhinitis: a double-blind placebo-controlled study. Eur Cytokine Netw 16:128–134Google Scholar
  42. 42.
    Dunford PJ, O’Donnell N, Riley JP et al (2006) The histamine H4 receptor mediates allergic airway inflammation by regulating the activation of CD4+ T cells. J Immunol 176:7062–7070CrossRefGoogle Scholar
  43. 43.
    Zhong H, Fan XL, Yu QN et al (2017) Increased innate type 2 immune response in house dust mite-allergic patients with allergic rhinitis. Clin Immunol 183:293–299CrossRefGoogle Scholar
  44. 44.
    Vannella KM, Ramalingam TR, Borthwick LA et al (2016) Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine-driven inflammation and fibrosis. Sci Transl Med 8:337ra65CrossRefGoogle Scholar
  45. 45.
    Kiss R, Keseru GM (2014) Novel histamine H4 receptor ligands and their potential therapeutic applications: an update. Expert Opin Ther Pat 24:1185–1197CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Schools of Medicine and Nursing SciencesHuzhou UniversityHuzhouChina

Personalised recommendations