Original Article
 

Decreased Circulating Interleukin-35 Levels Are Related to Interleukin-4-Producing CD8+ T Cells in Patients with Allergic Asthma

Abstract

Interleukin (IL)-35 is a newly discovered suppressive cytokine and has been shown to alleviate  inflammatory  and  autoimmune  diseases.  The  purpose  of  this  study  was  to investigate immunomodulatory capacity of IL-35 in patients with allergic asthma.IL-35 mRNA expression levels in peripheral blood mononuclear cells (PBMCs) were detected  by  quantitative  real-time  PCR  (qPCR).  The  frequencies  of  cytotoxic  T  cells (Tc)1,Tc2  and  Tc17  cells  were  measured  by  flow  cytometry.  Plasma  levels  of  IL-35, interferon (IFN)-γ, IL-4, and IL-17 were examined by enzyme-linked immunosorbent assay (ELISA). The correlations between plasma IL-35 levels and Tc1, Tc2, and Tc17 cytokine production in allergic asthmatics (n = 25) and healthy controls (n = 12) were analyzed by Pearson’s test.IL-35 protein and mRNA expression levels were down-regulated in allergic asthmatics compared with healthy controls. The frequencies of Tc2 and Tc17 cells were significantly increased in patients with asthma, and the frequency of Tc1 cells did not differ between asthmatic patients and healthy controls. Similarly, plasma levels of IL-4 and IL-17 were significantly increased in asthmatic patients, while there was no difference in IFN-γ levels between allergic asthma patients  and  healthy  controls.  More importantly,  plasma  IL-35 protein levels were negatively correlated with the frequency of IL-4-producing CD8+ T (Tc2) cells and with the IL-4 level in patients with allergic asthma.Our results suggest that decreased circulating IL-35 levels could contribute to the pathogenesis of allergic asthma by regulating CD8+ T cells.

1. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31(1):143-78.

2. Kay AB. The role of T lymphocytes in asthma. Chem Immunol Allergy 2006; 91:59-75.

3. Marsland BJ, Le Gros G. CD8+ T cells and immunoregulatory networks in asthma. Springer Semin Immunopathol 2004; 25(3-4):311-23.

4. O'Sullivan S, Cormican L, Faul JL, Ichinohe S, Johnston SL, Burke CM, et al. Activated, cytotoxic CD8(+) T lymphocytes contribute to the pathology of asthma death. Am J Respir Crit Care Med 2001; 164(4):560-4.

5. Betts RJ, Kemeny DM. CD8+ T cells in asthma: friend or foe? Pharmacol Ther 2009; 121(2):123-31.

6. Miyahara N, Swanson BJ, Takeda K, Taube C, Miyahara S, Kodama T, et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004; 10(8):865-9.

7. Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007;450(7169):566-9.

8. Vignali DA, Kuchroo VK. IL-12 family cytokines:immunological playmakers. Nat Immunol 2012;13(8):722-8.

9. Liu JQ, Liu Z, Zhang X, Shi Y, Talebian F, Carl JW, Jr., et al. Increased Th17 and regulatory T cell responses in EBV-induced gene 3-deficient mice lead to marginally enhanced development of autoimmune encephalomyelitis. J Immunol 2012; 188(7):3099-106.

10. Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 2010; 11(12):1093-101.

11. Kochetkova I, Golden S, Holderness K, Callis G, Pascual DW. IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol 2010; 184(12):7144-53.

12. Bettini M, Castellaw AH, Lennon GP, Burton AR, Vignali DA. Prevention of autoimmune diabetes by ectopic pancreatic beta-cell expression of interleukin-35. Diabetes 2012; 61(6):1519-26.

13. Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 2007;37(11):3021-9.

14. Huang CH, Loo EX, Kuo IC, Soh GH, Goh DL, Lee BW, et al. Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. J Immunol 2011; 187(1):462-71.

15. GINA. Global Strategy for Asthma Management and Prevention. 2014; Available from www.ginasthma.org.

16. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25(4):402-8.

17. Zhao Y, Yang J, Gao YD, Guo W. Th17 immunity in patients with allergic asthma. Int Arch Allergy Immunol 2010; 151(4):297-307.

18. Liu F, Tong F, He Y, Liu H. Detectable expression of IL-35 in CD4+ T cells from peripheral blood of chronic hepatitis B patients. Clin Immunol 2011; 139(1):1-5.

19. Cui G, Goll R, Olsen T, Steigen SE, Husebekk A, Vonen B, et al. Reduced expression of microenvironmental Th1 cytokines accompanies adenomas-carcinomas sequence of colorectum. Cancer Immunol Immunother 2007;56(7):985-95.

20. Wells JW, Cowled CJ, Giorgini A, Kemeny DM, Noble A. Regulation of allergic airway inflammation by class I- restricted allergen presentation and CD8 T-cell infiltration. J Allergy Clin Immunol 2007; 119(1):226-34.

21. Zhao Y, Yang J, Gao YD. Altered expressions of helper T cell (Th)1, Th2, and Th17 cytokines in CD8(+) and gammadelta T cells in patients with allergic asthma. J Asthma 2011; 48(5):429-36.

22. Li K, Wang Z, Cao Y, Bunjhoo H, Zhu J, Chen Y, et al.The study of the ratio and distribution of Th17 cells and Tc17 cells in asthmatic patients and the mouse model. Asian Pac J Allergy Immunol 2013; 31(2):125-31.

23. Bullens DM, Truyen E, Coteur L, Dilissen E, Hellings PW, Dupont LJ, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res 2006; 7:135.

24. Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol 2012; 129(1):207-15.

25. Ma Y, Liu X, Wei Z, Wang X, Xu D, Dai S, et al. The expression of a novel anti-inflammatory cytokine IL-35 and its possible significance in childhood asthma. Immunol Lett 2014; 162(1 Pt A):11-7.

Files
IssueVol 14, No 4 (2015) QRcode
SectionOriginal Article(s)
Keywords
Allergic asthma CD8 T cells Interleukin-4 Interleukin-35

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Wang W, Li P, Yang J. Decreased Circulating Interleukin-35 Levels Are Related to Interleukin-4-Producing CD8+ T Cells in Patients with Allergic Asthma. Iran J Allergy Asthma Immunol. 2015;14(4):379-385.