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Interleukin-17A up-regulates thymic stromal lymphopoietin production by nasal fibroblasts from patients with allergic rhinitis

  • Rhinology
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Purpose

Emerging evidence has shown that interleukin (IL)-17A is implicated in the pathogenesis of allergic rhinitis (AR). Thymic stromal lymphopoietin (TSLP) orchestrates the immune response toward a Th2 phenotype. Although increased TSLP is found in AR, the contribution of IL-17A in TSLP production by nasal fibroblasts is not well understood. We aimed to investigate the effect and mechanism of IL-17A on TSLP production by human nasal fibroblasts (HNFs) from AR patients.

Methods

HNFs from AR patients were cultured and stimulated with IL-17A in the absence or presence of a Janus kinase (JAK) 2 or JAK1/3 inhibitor. Western blotting was used to assay phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and nuclear factor-kappa B (NF-κB) p65 in HNFs. The TSLP expression in the cells and culture supernatants was evaluated by real-time polymerase chain reaction and enzyme-linked immunoassay.

Results

Stimulation with IL-17A induced STAT3 phosphorylation, which was inhibited by the pretreatment with JAK2 inhibitor AZD1480 or JAK1/3 inhibitor tofacitinib. IL-17A promoted the nuclear translocation of NF-κBp65 protein, leading to increased TSLP production, while the pre-incubation with AZD1480 prior to IL-17A attenuated these effects. However, the pre-incubation with tofacitinib before IL-17A stimulation had no impact on the expression of NF-κBp65 and TSLP.

Conclusions

IL-17A up-regulated TSLP production by HNFs through JAK2/NF-κB pathway. Although IL-17A induced STAT3 activation through JAK1/2/3, IL-17A-mediated TSLP expression was not dependent on STAT3 signaling. These observations would provide mechanistic insight into therapeutic strategies to improve the immune and inflammation associated with Th17A in the management of AR.

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References

  1. Brożek JL, Bousquet J, Agache I et al (2017) Allergic rhinitis and its impact on asthma (ARIA) guidelines-2016 revision. J Allergy Clin Immunol 140:950–958

    PubMed  Google Scholar 

  2. Zhu DC, Feng Y, Wang BQ (2019) Research progress on the relevance between serum vitamin D and IL-33/ST2 levels and allergic rhinitis. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 33:898–900

    CAS  PubMed  Google Scholar 

  3. Haitchi HM, Holgate ST (2004) New strategies in the treatment and prevention of allergic diseases. Expert Opin Investig Drugs 13:107–124

    CAS  PubMed  Google Scholar 

  4. Rochman Y, Dienger-Stambaugh K, Richgels PK et al (2018) TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state. Sci Signal 11:eaam8858

    PubMed  PubMed Central  Google Scholar 

  5. Liu YJ (2006) Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med 203:269–273

    PubMed  PubMed Central  Google Scholar 

  6. Mou Z, Xia J, Tan Y et al (2009) Overexpression of thymic stromal lymphopoietin in allergic rhinitis. Acta Otolaryngol 129:297–301

    CAS  PubMed  Google Scholar 

  7. 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 430:161–169

    CAS  PubMed  Google Scholar 

  8. Pan Z, Zhou Y, Luo X et al (2018) Against NF-κB/thymic stromal lymphopoietin signaling pathway, catechin alleviates the inflammation in allergic rhinitis. Int Immunopharmacol 61:241–248

    CAS  PubMed  Google Scholar 

  9. Nomura K, Kojima T, Fuchimoto J et al (2012) Regulation of interleukin-33 and thymic stromal lymphopoietin in human nasal fibroblasts by proinflammatory cytokines. Laryngoscope 122:1185–1192

    CAS  PubMed  Google Scholar 

  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 61:35–43

    CAS  PubMed  Google Scholar 

  11. Shin SH, Ye MK, Kim YH et al (2016) Role of TLRs in the production of chemical mediators in nasal polyp fibroblasts by fungi. Auris Nasus Larynx 43:166–170

    PubMed  Google Scholar 

  12. Kim JA, Cho JH, Park IH et al (2016) Diesel exhaust particles upregulate interleukins IL-6 and IL-8 in nasal fibroblasts. PLoS ONE 11:e0157058

    PubMed  PubMed Central  Google Scholar 

  13. Kato A (2019) Group 2 innate lymphoid cells in airway diseases. Chest 156:141–149

    PubMed  PubMed Central  Google Scholar 

  14. Albano GD, Di Sano C, Bonanno A et al (2013) Th17 immunity in children with allergic asthma and rhinitis: a pharmacological approach. PLoS ONE 8:e58892

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Louten J, Boniface K, de Waal MR (2009) Development and function of TH17 cells in health and disease. J Allergy Clin Immunol 123:1004–1011

    CAS  PubMed  Google Scholar 

  16. Liu Y, Zeng M, Liu Z (2015) Th17 response and its regulation in inflammatory upper airway diseases. Clin Exp Allergy 45:602–612

    CAS  PubMed  Google Scholar 

  17. Shahsavan S, Pirayesh A, Samani OZ et al (2019) The relationship between IL-17A and IL-22 expression and clinical severity in patients with moderate/severe persistent allergic rhinitis. Am J Otolaryngol 40:173–178

    PubMed  Google Scholar 

  18. Zhang YL, Han DH, Kim DY et al (2017) Role of interleukin-17A on the chemotactic responses to ccl7 in a murine allergic rhinitis model. PLoS ONE 12:e0169353

    PubMed  PubMed Central  Google Scholar 

  19. Makihara S, Okano M, Fujiwara T et al (2014) Local expression of interleukin-17a is correlated with nasal eosinophilia and clinical severity in allergic rhinitis. Allergy Rhinol (Providence) 5:22–27

    Google Scholar 

  20. Wang WW, Zhu K, Yu HW, Pan YL (2019) Interleukin-17A potentiates interleukin-13-induced eotaxin-3 production by human nasal epithelial cells from patients with allergic rhinitis. Int Forum Allergy Rhinol 9:1327–1333

    PubMed  Google Scholar 

  21. Ahn SH, Edwards AK, Singh SS et al (2015) IL-17A contributes to the pathogenesis of endometriosis by triggering proinflammatory cytokines and angiogenic growth factors. J Immunol 195:2591–2600

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Homma H, Kamiya K, Kusunoki T et al (2013) Multiplex analyses of cytokine and chemokine release from the cultured fibroblast of nasal polyps: the effect of IL-17A. Acta Otolaryngol 133:1065–1072

    CAS  PubMed  Google Scholar 

  23. Zhang J, Wang D, Wang L et al (2019) Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease. Am J Physiol Lung Cell Mol Physiol 316:L487–L497

    CAS  PubMed  Google Scholar 

  24. Bousquet J, Khaltaev N, Cruz AA et al (2008) Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 86:8–160

    Google Scholar 

  25. Amin K, Issa SM, Ali KM et al (2018) The effect of urban particulate matter on cultured human nasal fibroblasts. Int Forum Allergy Rhinol 8:993–1000

    Google Scholar 

  26. Nonaka M, Ogihara N, Fukumoto A et al (2009) Synergistic induction of macrophage inflammatory protein-3α;/CCL20 production by interleukin-17A and tumor necrosis factor-α; in nasal polyp fibroblasts. World Allergy Organ J 2:218–223

    PubMed  PubMed Central  Google Scholar 

  27. Lennox AT, Coburn SL, Leech JA et al (2018) ATP12A promotes mucus dysfunction during type 2 airway inflammation. Sci Rep 8:2109

    PubMed  PubMed Central  Google Scholar 

  28. Shin SH, Kim YH, Jin HS et al (2016) Alternaria induces production of thymic stromal lymphopoietin in nasal fibroblasts through toll-like receptor 2. Allergy Asthma Immunol Res 8:63–68

    CAS  PubMed  Google Scholar 

  29. Gu ZW, Wang YX, Cao ZW (2017) Neutralization of interleukin-17 suppresses allergic rhinitis symptoms by downregulating Th2 and Th17 responses and upregulating the treg response. Oncotarget 8:22361–22369

    PubMed  PubMed Central  Google Scholar 

  30. Saleh A, Shan L, Halayko AJ et al (2009) Critical role for STAT3 in IL-17A mediated CCL11 expression in human airway smooth muscle cells. J Immunol 182:3357–3365

    CAS  PubMed  Google Scholar 

  31. Chen Y, Kijlstra A, Chen Y et al (2011) IL-17A stimulates the production of inflammatory mediators via Erk1/2, p38 MAPK, PI3K/Akt, and NF-B pathways in ARPE-19 cells. Mol Vis 17:3072–3077

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Miossec P, Kolls JK (2012) Targeting IL-17 and TH1 cells in chronic inflammation. Nat Rev Drug Discov 11:763–776

    CAS  PubMed  Google Scholar 

  33. Huang F, Kao CY, Wachi S et al (2007) Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. J Immunol 179:6504–6513

    CAS  PubMed  Google Scholar 

  34. Yu X, He L, Cao P, Yu Q (2015) Eriocalyxin B inhibits stat3 signaling by covalently targeting STAT3 and blocking phosphorylation and activation of STAT3. PLoS ONE 10:e0128406

    PubMed  PubMed Central  Google Scholar 

  35. Shan L, Redhu NS, Saleh A et al (2010) Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways. J Immunol 184:7134–7143

    CAS  PubMed  Google Scholar 

  36. Simeone-Penney MC, Severgnini M, Tu P et al (2007) Airway epithelial STAT3 is required for allergic inflammation in a murine model of asthma. J Immunol 178:6191–6199

    CAS  PubMed  Google Scholar 

  37. Redhu NS, Shan L, Movassagh H et al (2013) Thymic stromal lymphopoietin induces migration in human airway smooth muscle cells. Sci Rep 3:2301

    PubMed  PubMed Central  Google Scholar 

  38. Watson B, Gauvreau GM (2014) Thymic stromal lymphopoietin: a central regulator of allergic asthma. Expert Opin Ther Targets 18:771–785

    CAS  PubMed  Google Scholar 

  39. Sun Q, Liu Y, Zhang S et al (2015) Thymic stromal lymphopoietin polymorphisms and allergic rhinitis risk: a systematic review and meta-analysis with 6351 cases and 11472 controls. Int J Clin Exp Med 8:15752–15758

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gauvreau GM, O’Byrne PM, Boulet LP et al (2014) Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 370:2102–2110

    PubMed  Google Scholar 

  41. Digicaylioglu M, Lipton SA (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412:641–647

    CAS  PubMed  Google Scholar 

  42. Funakoshi-Tago M, Tago K, Sato Y et al (2011) JAK2 is an important signal transducer in IL-33-induced NF-κB activation. Cell Signal 23:363–370

    CAS  PubMed  Google Scholar 

  43. Lee HC, Ziegler SF (2007) Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFkappaB. Proc Natl Acad Sci U S A 104:914–919

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang WW, Pan YL, Yu HW et al (2019) Histamine H4 receptor regulates Th2-cytokine profile through thymic stromal lymphopoietin in allergic rhinitis. Eur Arch Otorhinolaryngol 276:1655–1661

    PubMed  Google Scholar 

  45. Wang WW, Zhu K, Yu HW et al (2019) Interleukin-17A potentiates interleukin-13-induced eotaxin-3 production by human nasal epithelial cells from patients with allergic rhinitis. Int Forum Allergy Rhinol 9:1327–1333

    PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Public Welfare Technology Application Research Project of Zhejiang Province, China (2017C37146).

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Authors and Affiliations

  1. Key Laboratory of Vector Biology and Pathogen Control of Zhejiang Province, Huzhou Central Hospital, School of Medicine, Huzhou University, No. 759, East Second Ring Road, Huzhou, 313000, Zhejiang, China

    Wei Wei Wang

  2. School of Medicine, Huzhou University, No. 759, East Second Ring Road, Huzhou, 313000, Zhejiang, China

    Hong Wei Yu, Bo Zhang, Yong Liang Pan & Sheng Wen Shao

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  1. Wei Wei Wang
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Contributions

WWW: drafting the article. HWY: revising the article critically for important intellectual content. BZ: substantial contributions to conception and design, acquisition of data. YLP: analysis and interpretation of data. SWS: 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.

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Correspondence to Sheng Wen Shao.

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Conflict of interest

No financial conflicts of interests exist. This study was supported by the Public Welfare Technology Application Research Project of Zhejiang Province, China (No. 2017C37146).

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The ethics committee in which all authors worked approved this study. All participants signed informed consent.

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Wang, W.W., Yu, H.W., Zhang, B. et al. Interleukin-17A up-regulates thymic stromal lymphopoietin production by nasal fibroblasts from patients with allergic rhinitis. Eur Arch Otorhinolaryngol 278, 127–133 (2021). https://doi.org/10.1007/s00405-020-06274-3

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