IL‑22/IL‑22R1 promotes proliferation and collagen synthesis of MRC‑5 cells via the JAK/STAT3 signaling pathway and regulates airway subepithelial fibrosis

Liu,Juan; Shang,Biao; Bai,Jing

doi:10.3892/etm.2020.8931

IL‑22/IL‑22R1 promotes proliferation and collagen synthesis of MRC‑5 cells via the JAK/STAT3 signaling pathway and regulates airway subepithelial fibrosis

Authors:
- Juan Liu
- Biao Shang
- Jing Bai
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Affiliations: Department of Pediatrics, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
Published online on: June 24, 2020 https://doi.org/10.3892/etm.2020.8931
Pages: 2148-2156
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Asthma in children poses a threat to their health, but the mechanism remains to be elucidated. The present study investigated the mechanism by which the interleukin (IL)‑22/IL‑22 receptor 1 (IL‑22R1) signaling pathway regulates subepithelial fibrosis in children with asthma. A total of 41 children with asthma and 12 healthy children were included in the present study. ELISA was performed to measure the content of IL‑22 in peripheral blood. Serum from children with asthma was used to incubate MRC‑5 cells and IL‑22 antibody rescued the effect of IL‑22 on the biological functions of MRC‑5 cells. Reverse transcription‑quantitative PCR was performed to determine IL‑22R1 mRNA expression levels and western blotting was performed to measure IL‑22R1 protein expression. The Cell Counting Kit‑8 assay was used to analyze cell proliferation and flow cytometry was performed to assess the cell cycle distribution of MRC‑5 cells. The expression of IL‑22 was elevated in peripheral blood from children with asthma, which promoted the proliferation of MRC‑5 cells, possibly via the upregulation of collagen type I α1 chain (COL1α1) and collagen type I α2 chain (COL1α2). IL‑22 exerted its biological functions via IL‑22R1. The IL‑22/IL‑22R1 signaling pathway regulated the proliferation of MRC‑5 cells and the expression of COL1α1 and COL1α2 in MRC‑5 cells via the JAK/STAT3 signaling pathway. Mononuclear lymphocytes from children with asthma stimulated the proliferation and secretory function of fibroblasts by secreting IL‑22. The present study suggested that IL‑22 expression in peripheral blood of children with asthma is upregulated compared with the control group. Furthermore, the present study indicated that the IL‑22/IL‑22R1 signaling pathway promoted MRC‑5 cell proliferation and collagen synthesis by activating the JAK/STAT3 signaling pathway, thereby potentially regulating airway subepithelial fibrosis.

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1	Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, Merid SK, Rezwan FI, Page CM, Ullemar V, et al: Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J Allergy Clin Immunol. 143:2062–2074. 2019.PubMed/NCBI View Article : Google Scholar
2	Saglani S and Custovic A: Childhood asthma: Advances using machine learning and mechanistic studies. Am J Respir Crit Care Med. 199:414–422. 2019.PubMed/NCBI View Article : Google Scholar
3	Eldeirawi K, Kunzweiler C, Zenk S, Finn P, Nyenhuis S, Rosenberg N and Persky V: Associations of urban greenness with asthma and respiratory symptoms in Mexican American children. Ann Allergy Asthma Immunol. 122:289–295. 2019.PubMed/NCBI View Article : Google Scholar
4	Kim YM, Kim J, Cheong HK, Jeon BH and Ahn K: Exposure to phthalates aggravates pulmonary function and airway inflammation in asthmatic children. PLoS One. 13(e0208553)2018.PubMed/NCBI View Article : Google Scholar
5	Biagini Myers JM, Schauberger E, He H, Martin LJ, Kroner J, Hill GM, Ryan PH, LeMasters GK, Bernstein DI, Lockey JE, et al: A pediatric asthma risk score to better predict asthma development in young children. J Allergy Clin Immunol. 143:1803–1810.e2. 2019.PubMed/NCBI View Article : Google Scholar
6	Lezmi G and de Blic J: Assessment of airway inflammation and remodeling in children with severe asthma: The next challenge. Pediatr Pulmonol. 53:1171–1173. 2018.PubMed/NCBI View Article : Google Scholar
7	Fehrenbach H, Wagner C and Wegmann M: Airway remodeling in asthma: What really matters. Cell Tissue Res. 367:551–569. 2017.PubMed/NCBI View Article : Google Scholar
8	Kumari A, Singh DK, Dash D and Singh R: Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model. Inflammopharmacology. 27:731–748. 2019.PubMed/NCBI View Article : Google Scholar
9	Lin SC, Chou HC, Chen CM and Chiang BL: Anti-thymic stromal lymphopoietin antibody suppresses airway remodeling in asthma through reduction of MMP and CTGF. Pediatr Res. 86:181–187. 2019.PubMed/NCBI View Article : Google Scholar
10	Zhou J, Bai W, Liu Q, Cui J and Zhang W: Silencing of ADAM33 restrains proliferation and induces apoptosis of airway smooth muscle cells in ovalbumin-induced asthma model. J Cell Biochem, Nov 18, 2018 (Epub ahead of print).
11	Cao L, Liu F, Liu Y, Liu T, Wu J, Zhao J, Wang J, Li S, Xu J and Dong L: TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast. Exp Lung Res. 44:288–301. 2018.PubMed/NCBI View Article : Google Scholar
12	Yadav SK, Shah SD and Penn RB: Give me a fork: Can autophagy research solve the riddle of airway remodeling in asthma? Am J Respir Cell Mol Biol. 60:494–496. 2019.PubMed/NCBI View Article : Google Scholar
13	Kaczmarek KA, Clifford RL and Knox AJ: Epigenetic changes in airway smooth muscle as a driver of airway inflammation and remodeling in asthma. Chest. 155:816–824. 2019.PubMed/NCBI View Article : Google Scholar
14	Rodrigues APD, Bortolozzo ASS, Arantes-Costa FM, Saraiva-Romanholo BM, de Souza FCR, Brüggemann TR, Santana FPR, de Brito MV, Bonturi CR, Nunes NNDS, et al: A plant proteinase inhibitor from enterolobium contortisiliquum attenuates airway hyperresponsiveness, inflammation and remodeling in a mouse model of asthma. Histol Histopathol. 34:537–552. 2019.PubMed/NCBI View Article : Google Scholar
15	McAlinden KD, Deshpande DA, Ghavami S, Xenaki D, Sohal SS, Oliver BG, Haghi M and Sharma P: Autophagy activation in asthma airways remodeling. Am J Respir Cell Mol Biol. 60:541–553. 2019.PubMed/NCBI View Article : Google Scholar
16	Brunner PM, Pavel AB, Khattri S, Leonard A, Malik K, Rose S, Jim On S, Vekaria AS, Traidl-Hoffmann C, Singer GK, et al: Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. J Allergy Clin Immunol. 143:142–154. 2019.PubMed/NCBI View Article : Google Scholar
17	Leyva-Castillo JM, Yoon J and Geha RS: IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice. J Allergy Clin Immunol. 143:619–630.e7. 2019.PubMed/NCBI View Article : Google Scholar
18	Geng H, Bu HF, Liu F, Wu L, Pfeifer K, Chou PM, Wang X, Sun J, Lu L, Pandey A, et al: In inflamed intestinal tissues and epithelial cells, interleukin 22 signaling increases expression of H19 long noncoding RNA, which promotes mucosal regeneration. Gastroenterology. 155:144–155. 2018.PubMed/NCBI View Article : Google Scholar
19	Chen E, Cen Y, Lu D, Luo W and Jiang H: IL-22 inactivates hepatic stellate cells via downregulation of the TGF-β1/Notch signaling pathway. Mol Med Rep. 17:5449–5453. 2018.PubMed/NCBI View Article : Google Scholar
20	Almolda B, Costa M, Montoya M, González B and Castellano B: Increase in Th17 and T-reg lymphocytes and decrease of IL22 correlate with the recovery phase of acute EAE in rat. PLoS One. 6(e27473)2011.PubMed/NCBI View Article : Google Scholar
21	Pollock RA, Zaman L, Chandran V and Gladman DD: Epigenome-wide analysis of sperm cells identifies IL22 as a possible germ line risk locus for psoriatic arthritis. PLoS One. 14(e0212043)2019.PubMed/NCBI View Article : Google Scholar
22	He Y, Yang Y, Xu J, Liao Y, Liu L, Deng L and Xiong X: IL22 drives cutaneous melanoma cell proliferation, migration and invasion through activation of miR-181/STAT3/AKT axis. J Cancer. 11:2679–2687. 2020.PubMed/NCBI View Article : Google Scholar
23	Bao Y: Guidelines for the diagnosis and treatment of bronchial asthma in children (2016 edition). Data Collection of the 20th National Pediatric Academic Conference on Integration of Traditional Chinese and Western Medicine: 57-71, 2016.
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
25	Campa CC, Silva RL, Margaria JP, Pirali T, Mattos MS, Kraemer LR, Reis DC, Grosa G, Copperi F, Dalmarco EM, et al: Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Nat Commun. 9(5232)2018.PubMed/NCBI View Article : Google Scholar
26	Sun Q, Fang L, Tang X, Lu S, Tamm M, Stolz D and Roth M: TGF-β upregulated mitochondria mass through the SMAD2/3→C/EBPβ→PRMT1 signal pathway in primary human lung fibroblasts. J Immunol. 202:37–47. 2019.PubMed/NCBI View Article : Google Scholar
27	Reeder KM, Mackel JJ, Godwin MS, Dunaway CW, Blackburn JP, Patel RP and Steele C: Role of common γ-Chain cytokines in lung interleukin-22 regulation after acute exposure to aspergillus fumigatus. Infect Immun. 86:e00157–18. 2018.PubMed/NCBI View Article : Google Scholar
28	Trevejo-Nunez G, Elsegeiny W, Conboy P, Chen K and Kolls JK: Critical role of IL-22/IL22-RA1 signaling in pneumococcal pneumonia. J Immunol. 197:1877–1883. 2016.PubMed/NCBI View Article : Google Scholar
29	Khosravi N, Caetano MS, Cumpian AM, Unver N, De la Garza Ramos C, Noble O, Daliri S, Hernandez BJ, Gutierrez BA, Evans SE, et al: IL22 promotes kras-mutant lung cancer by induction of a protumor immune response and protection of stemness properties. Cancer Immunol Res. 6:788–797. 2018.PubMed/NCBI View Article : Google Scholar
30	Rompré-Brodeur A, Shinde-Jadhav S, Ayoub M, Piccirillo CA, Seuntjens J, Brimo F, Mansure JJ and Kassouf W: PD-1/PD-L1 immune checkpoint inhibition with radiation in bladder cancer: In situ and abscopal effects. Mol Cancer Ther. 19:211–220. 2020.PubMed/NCBI View Article : Google Scholar
31	Zhou Y, Hou W, Xu K, Han D, Jiang C, Mou K, Li Y, Meng L and Lu S: The elevated expression of Th17-related cytokines and receptors is associated with skin lesion severity in early systemic sclerosis. Hum Immunol. 76:22–29. 2015.PubMed/NCBI View Article : Google Scholar
32	He W, Wu J, Shi J, Huo YM, Dai W, Geng J, Lu P, Yang MW, Fang Y, Wang W, et al: IL22RA1/STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer. Cancer Res. 78:3293–3305. 2018.PubMed/NCBI View Article : Google Scholar
33	Khare V, Paul G, Movadat O, Frick A, Jambrich M, Krnjic A, Marian B, Wrba F and Gasche C: IL10R2 overexpression promotes IL22/STAT3 signaling in colorectal carcinogenesis. Cancer Immunol Res. 3:1227–1235. 2015.PubMed/NCBI View Article : Google Scholar
34	Eggenhofer E, Sabet-Rashedi M, Lantow M, Renner P, Rovira J, Koehl GE, Schlitt HJ, Geissler EK and Kroemer A: RORγt(+) IL-22-producing NKp46(+) cells protect from hepatic ischemia reperfusion injury in mice. J Hepatol. 64:128–134. 2016.PubMed/NCBI View Article : Google Scholar