Background: Suppressor of cytokine signaling 1 (SOCS1) and SOCS3 play important roles in T helper cell differentiation, which is involved with the pathologic mechanisms of allergic rhinitis (AR). The aim of this study was to evaluate the expression of SOCS1 and SOCS3 in AR and find their regulatory microRNAs (miRNAs) to provide a basis for the treatment of AR. Methods: The expression of SOCS1 and SOCS3 were analyzed by real-time PCR, immunohistochemistry, and Western blot. The correlative regulatory miRNAs were detected by real-time PCR. Luciferase assays and AR mouse model experiments were applied to identify correlative miRNAs that target SOCS3. Results: SOCS1 and SOCS3 mRNA were upregulated in the nasal mucosa and peripheral blood mononuclear cells of AR compared with controls. The expression of SOCS3 protein was significantly increased in the nasal mucosa of AR. The immunohistochemical staining results showed that SOCS3 was similarly localized in the superficial epithelium, submucosal glands, and vascular endothelium in the nasal mucosa of AR subjects and controls. However, SOCS3 protein was especially localized in the inflammatory cells, such as eosinophils, monocytes, and lymphocytes. Conclusions: SOCS3 was targeted by miR30a- 5p in AR. Further study should be performed to identify the regulatory effect of miR30a-5p in AR, which may provide insights into a new therapeutic strategy.

1.
Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, TogiasA, et al: Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA2LEN and AllerGen). Allergy 2008; 63(suppl 86): 8–160.
2.
Kariyawasam HH, Rotiroti G: Allergic rhinitis, chronic rhinosinusitis and asthma: unravelling a complex relationship. Curr Opin Otolaryngol Head Neck Surg 2013; 21: 79–86.
3.
Knisz J, Rothman PB: Suppressor of cytokine signaling in allergic inflammation. J Allergy Clin Immunol 2007; 119: 739–745.
4.
Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A: Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 2011; 31: 980–985.
5.
Lemmon MA, Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell 2010; 141: 1117–1134.
6.
Lu TX, Rothenberg ME: Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. J Allergy Clin Immunol 2013; 132: 3–13.
7.
Rebane A, Akdis CA: MicroRNAs in allergy and asthma. Curr Allergy Asthma Rep 2014; 14: 424.
8.
Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B: Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol 2011,128: 1077–1085.
9.
Chen RF, Huang HC, Ou CY, Hsu TY, Chuang H, Chang JC, Wang L, Kuo HC, Yang KD: MicroRNA-21 expression in neonatal blood associated with antenatal immunoglobulin E production and development of allergic rhinitis. Clin Exp Allergy 2010; 40: 1482–1490.
10.
Teng Y, Zhang R, Liu C, Zhou L, Wang H, Zhang W, Huang Y, Hong Z: miR-143 inhibits interleukin-13-induced inflammatory cytokine and mucus production in nasal epithelial cells from allergic rhinitis patients by targeting IL13Rα1. Biochem Biophys Res Commun 2015; 457: 58–64.
11.
Deng YQ, Yang YQ, Wang SB, Li F, Liu MZ, Hua QQ, Tao ZZ: Intranasal administration oflentiviral miR-135a regulates mast cell and allergen-induced inflammation by targeting GATA-3. PLoS One 2015; 10:e0139322.
12.
Suojalehto H; Toskala E, Kilpeläinen M, Majuri ML, Mitts C, Lindström I, Puustinen A, Plosila T, Sipilä J, Wolff H, Alenius H: MicroRNA profiles in nasal mucosa of patients with allergic and nonallergic rhinitis and asthma. Int Forum Allergy Rhinol 2013; 3: 612–620.
13.
Lu LF, Thai TH, Calado DP, Chaudhry A, Kubo M, Tanaka K, Loeb GB, Lee H, Yoshimura A, Rajewsky K, Rudensky AY: Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 2009; 30: 80–91.
14.
Yao R, Ma YL, Liang W, Li HH, Ma ZJ, Yu X, Liao YH: MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS One 2012; 7:e46082.
15.
Quan SH, Zhang YL, Han DH, IwakuraY, Rhee CS: Contribution of interleukin-17A to the development and regulationof allergic inflammation in amurine allergic rhinitis model. Ann Allergy Asthma Immunol 2012; 108: 342–50.
16.
Baumann R, Rabaszowski M, Stenin I, Tilgner L, Scheckenbach K, Wiltfang J, Schipper J, Chaker A, Wagenmann M: Comparison of the nasal releaseof IL-4, IL-10, IL-17, CCL13/MCP-4, and CCL26/eotaxin-3 in allergic rhinitisduring season and after allergen challenge. Am J Rhinol Allergy 2013; 27: 266–272.
17.
Liu Y, Yu HJ, Wang N, Zhang YN, Huang SK, Cui YH, Liu Z: Clara cell 10-kDa protein inhibits TH17responses through modulating dendritic cells in the setting of allergic rhinitis. J Allergy Clin Immunol 2013; 131: 387–394.
18.
Pawankar R, Hayashi M, Yamanishi S, Igarashi T: The paradigm of cytokine networks in allergic airway inflammation. Curr Opin Allergy Clin Immunol 2015; 15: 41–48.
19.
Fujimoto M, Tsutsui H, Yumikura-Futatsugi S, Ueda H, Xingshou O, Abe T, Kawase I, Nakanishi K, Kishimoto T, Naka T: A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo. Int Immunol 2002; 14: 1343–1350.
20.
Tanaka K, Ichiyama K, Hashimoto M, Yoshida H, Takimoto T, Takaesu G, Torisu T, Hanada T, Yasukawa H, Fukuyama S, Inoue H, Nakanishi Y, Kobayashi T, Yoshimura A: Loss of suppressor of cytokine signaling 1 in helper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFNγ on STAT3 and Smads. J Immunol 2008; 180: 3746–3756.
21.
Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K,Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O’Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M: SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nat Med 2003; 9: 1047–1054.
22.
Chen Z, Laurence A, Kanno Y, Pacher-Zavisin M, Zhu BM, Tato C, Yoshimura A, Hennighausen L, O’Shea JJ: Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 2006; 103: 8137–8142.
23.
Wong PK, Egan PJ, Croker BA, O’Donnell K, Sims NA, Drake S, Kiu H, McManus EJ, Alexander WS, Roberts AW, Wicks IP: SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J Clin Invest 2006; 116: 1571–1581.
24.
Shouda T, Yoshida T, Hanada T,Wakioka T, Oishi M, Miyoshi K,Komiya S, Kosai K, Hanakawa Y, Hashimoto K, Nagata K, Yoshimura A: Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 2001; 108: 1781–1788.
25.
Isomäki P, Alanärä T, Isohanni P, Lagerstedt A, Korpela M, Moilanen T, Visakorpi T, Silvennoinen O: The expression of SOCS is altered in rheumatoid arthritis. Rheumatology 2007; 46: 1745–1746.
26.
Lai NS, Chou JL, Chen GC, Chan MW, Liu SQ, Lu MC, Chan MW: Association between cytokines and methylation of SOC S-1 in serum of patients with ankylosing spondylitis. Mol Biol Rep 2014; 41: 3773–3780.
27.
Suzuki, A. Hanada T, Mitsuyama K, Yoshida T, Kamizono S, Hoshino T, Kubo M, Yamashita A, Okabe M, Takeda K, Akira S, Matsumoto S, Toyonaga A, Sata M, Yoshimura A: CIS3/SOCS3/SSI3 plays a negative regulatory role in STAT3 activation and intestinal inflammation. J Exp Med 2001; 193: 471–481.
28.
Miyanaka Y, Ueno Y, Tanaka S, Yoshioka K, Hatakeyama T, Shimamoto M, Sumii M, Chayama K: Clinical significance of mucosal suppressors of cytokine signaling 3 expression in ulcerative colitis. World J Gastroenterol 2007; 13: 2939–2944.
29.
Park Se Jin, Kim Tae Hoon, Jun Young Joon, Lee SeungHoon, Ryu Hyei Yul, Jung Kwang Jin, Jung Jong Yoon, Hwang GyuHo, Lee Sang Hag: Chronic rhinosinusitis with polyps and without polyps is associated with increased expression of suppressors of cytokine signaling 1 and 3. J Allergy Clin Immunol 2013; 131: 772–780.
30.
Federici M, Giustizieri ML, Scarponi C, Girolomoni G, Albanesi C: Impaired IFN-γ-dependent inflammatory responses in human keratinocytes overexpressing the suppressor of cytokine signaling 1. J Immunol 2002; 169: 434–442.
31.
Arakawa S, Hatano Y, Katagiri K: Differential expression of mRNA for Th1 and Th2 cytokine-associated transcription factors and suppressors of cytokine signalling in peripheral blood mononuclear cells of patients with atopic dermatitis. Clin Exp Immunol 2004; 135: 505–510.
32.
Harada M, Nakashima K, Hirota T, Shimizu M, Doi S, Fujita K, Shirakawa T, Enomoto T, Yoshikawa M, Moriyama H, Matsumoto K, Saito H, Suzuki Y, Nakamura Y, Tamari M: Functional polymorphism in the suppressor of cytokine signaling 1 gene associated with adult asthma. Am J Respir Cell Mol Biol 2007; 36: 491–496.
33.
Ozaki A, Seki Y, Fukushima A, Kubo M: The control of allergic conjunctivitis by suppressor of cytokine signaling SOCS3 and SOCS5 in a murine model. J Immunol 2005; 175: 5489–5497.
34.
Paul B, Mishra V, Chaudhury B, Raisuddin S: Status of Stat3 in an ovalbumin-induced mouse model of asthma: analysis of the role of Socs3 and IL-6. Int Arch Allergy Immunol 2009; 2: 99–108.
35.
Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O’Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M: SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nat Med 2003; 9: 1047–1054.
36.
Kim TH, Kim K, Park SJ, Lee SH, Hwang JW, Park SH, Yum GH, Lee SH: Expression of SOCS1 and SOCS3 is altered in the nasal mucosa of patients with mild and moderate/severe persistent allergic rhinitis. Int Arch Allergy Immunol 2012; 158: 387–396.
37.
Yoshimura A, Suzuki M, Sakaguchi R, Hanada T, Yasukawa H: SOCS, inflammation, and autoimmunity. Front Immunol 2012; 12: 20.
38.
López E, Zafra MP, Sastre B, Gámez C, Fernández-Nieto M, Sastre J, Lahoz C, Quirce S, Del Pozo V: Suppressors of cytokine signaling 3 expression in eosinophils: regulation by PGE₂ and Th2 cytokines. Clin Dev Immunol 2011; 2011: 917015.
39.
Yang C, Zheng C, Lin H, Li J, Zhao K: Role of suppressor of cytokine signaling 3 in the immune modulation of mesenchymal stromal cells. Inflammation 2016; 9: 257–268.
40.
Liu Y, Stewart KN, Bishop E, Marek CJ, Kluth DC, Rees AJ, Wilson HM: Unique expression of suppressor of cytokine signaling 3 is essential for classical macrophage activation in rodents in vitro and in vivo. J Immunol 2008; 180: 6270–6278.
41.
Kubo M, Hanada T, Yoshimura A: Suppressors of cytokine signaling and immunity. Nat Immunol 2003; 4: 1169–1176.
42.
Collison A, Herbert C, Siegle JS, Mattes J, Foster PS, Kumar RK: Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm Med 2011; 11: 29.
43.
Solberg OD, Ostrin EJ, Love MI, Peng JC, Bhakta NR, Hou L, Nguyen C, Solon M, Nguyen C, Barczak AJ, Zlock LT, Blagev DP, Finkbeiner WE, Ansel KM, Arron JR, Erle DJ, Woodruff PG: Airway epithelial miRNA expression is altered in asthma. Am J Respir Crit Care Med 2012; 186: 965–974.
44.
Ma L, Xue H B, Wang F, Shu CM, Zhang JH: MicroRNA-155 may be involved in the pathogenesis of atopic dermatitis by modulating the differentiation and function of T helper type 17 (Th17) cells. Clin Exp Immunol 2015; 181: 142–149.
45.
Wang, P, Hou J, Lin L, Wang C, Liu X, Li D, Ma F, Wang Z, Cao X: Inducible micro-RNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol 2010; 185: 6226–6233.
46.
Yu Y, Cao L, Yang L, Kang R, Lotze M, Tang D: MicroRNA 30A promotes autophagy in response to cancer therapy. Autophagy 2012; 8: 853–855.
47.
Li W, Liu C, Zhao C, Zhai L, Lv S: Downregulation of β3 integrin by miR-30a-5p modulates cell adhesion and invasion by interrupting Erk/Ets-1 network in triple-negative breast cancer. Int J Oncol 2016; 48: 1155–1164.
48.
Zhang L, Zhang XW, Liu CH, Xu B: MiRNA-30a functions as a tumor suppressor by downregulating cyclin E2 expression in castration-resistant prostate cancer. Mol Med Report 2016; 14: 2077–2084.
49.
Liu YX, Wang L, Liu WJ, Zhang HT, Xue JH, Zhang ZW, Gao CJ: MiR-124–3p/B4GALT1 axis plays an important role in SOCS3-regulated growth and chemo-sensitivity of CML. J Hematol Oncol 2016; 9: 69.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.