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Interleukin-31 Promotes Helper T Cell Type-2 Inflammation in Children with Allergic Rhinitis

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Interleukin-31 Promotes Helper T Cell Type-2 Inflammation in Children with Allergic Rhinitis nature publishing group Articles Basic Science Investigation Interleukin-31 promotes helper T cell type-2 inflammation in children with allergic rhinitis Wenlong Liu1, Renzhong Luo1, Yanqiu Chen1, Changzhi Sun1, Jie Wang1, Lifeng Zhou1, Yan Li1 and Li Deng1 BACKGROUND: Interleukin-31 (IL-31) is a recently described normal and disease state, such as activated CD4+ T cells, mast cytokine that is involved in helper T cell type-2 (Th2)-mediated cells, monocytes, macrophages, immature and mature mono- diseases. However, its regulatory effect in the pathogenesis of cyte-derived dendritic cells and so on (7). The receptor of IL-31 children allergic rhinitis (AR) needs to be further characterized. consists of IL-31 receptor A (IL-31RA) and the oncostatin M This study sought to evaluate the expression and role of IL-31 receptor that is constitutively expressed on epithelial cells (8). in children with AR. The role of IL-31 in allergic diseases mainly focused on atopic METHODS: Sixty children with AR and 20 normal controls dermatitis. Stephan et al. reported elevated IL-31 expression were included. IL-31 and Th2 cytokines production in tissue, in atopic dermatitis (9). UIrike et al. found a correlation of serum, and nasal lavage was examined by immunohisto- Th2 cytokines with increased level of IL-31 in children with chemistry, quantitative polymerase chain reaction (qPCR), and extrinsic atopic dermatitis (10). However, studies on respira- enzyme-linked immunosorbent assay, respectively. Peripheral tory allergic diseases are relatively few. Recently, Lei et al. (11) blood mononuclear cells (PBMCs) were purified for in vitro reg- reported that high IL-31 level in asthmatic subjects, suggest- ulation experiment of IL-31. Nasal epithelial cells (NECs) were ing that IL-31 may be a useful indicator of asthma. Moreover, cultured and stimulated by recombinant IL-31. IL-31 was found to be closely associated with IgE production RESULTS: The IL-31 mRNA and protein levels in both serum in asthmatic patients (12). Besides, IL-31 may play an impor- and nasal lavage were significantly enhanced in AR compared tant role in mucus overproduction in AR (13). with normal controls, especially in children with asthma. The Growing evidences suggest a positive role for IL-31 in Th2- nasal IL-31 was associated with enhanced local Th2 cytokines linked AR. Thus, our study was undertaken to determine the and mucin 5AC (MUC5AC) expression. In vitro study showed expression and role of IL-31 in children with AR accompanied that IL-31 promotes Th2 cytokines expression and MUC5AC with or without asthma. upregulation and thus amplified Th2 inflammation. CONCLUSION: Our results demonstrate that IL-31 expres- RESULTS sion in AR aggravated and amplified Th2 inflammation as well Demographic and Laboratory Characteristics of the Study as mucin production, and provide a possible explanation for Population IL-31’s regulatory role in the pathogenesis of AR. This study was conducted with 80 children, 60 of whom suffered from AR, with ages ranging between 19 and 185 mo (mean age: 77.7 ± 39.0 mo, 28 males), and 20 of whom were healthy controls llergic rhinitis (AR) is a common nasal disease and affects with ages ranging between 15 and 182 mo (mean age: 73.0 ± 36.8 A10–40% of children with increasing prevalence (1,2). AR mo, 11 males). The demographic features andlaboratory ­ param- frequently coexists with asthma (most studies report a rate of eters of the population are presented in Table 1. Asthma was 50–60%) in children (3). The major histological features of AR found to be 30% in the AR group. When the two groups were include helper T cell type-2 (Th2) inflammation accompanied by compared, the basophil count, the eosinophil count, total serum infiltration with eosinophils, allergen-specifc IgE production, IgE, and eosinophil cationic protein (ECP) levels were found to and thickening of the basement membrane (4,5). Activation of be higher in the AR group, than those of the control group, espe- Th2 cells and further released cytokines induced accumulation cially in children with asthma. of infammatory cells, such as B cells, plasma cells, eosinophils, basophils, and neutrophils, which contributed to the occurrence Increased Serum and Local IL-31 mRNA and Protein Levels as of AR (6). Despite involvement of Th2 infammation in AR was Well as Th2 Cytokines Protein in AR clearly clarifed, its regulation was not fully understood. The serum and local IL-31 mRNA and protein expression in Interleukin-31 (IL-31) is a newly discovered four-helix bun- AR were signifcantly higher than those in the normal con- dle cytokine and expressed by several types of cells under both trols, especially in those children with asthma (P = 0.001, The first three authors contributed equally to this work. 1Department of Otolaryngology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical College, Guangzhou, China. Correspondence: Renzhong Luo (renzhon- [email protected]) or Li Deng ([email protected]) Received 26 November 2013; accepted 22 July 2014; advance online publication 29 October 2014. doi:10.1038/pr.2014.151 20 Pediatric Research Volume 77 | Number 1 | January 2015 Copyright © 2015 International Pediatric Research Foundation, Inc. IL-31 in children with allergic rhinitis Articles Figure 1a–d). We also compared IL-31 expression between AR Figure 2m). Nasal IL-4, IL-5, IL-13, and MUC5AC were posi- children who are >6 y and <6 y and no differences were found tively correlated with local IL-31, respectively (Figure 3a–d). (data not shown). Our results showed that enhanced protein The serum ECP and IgE levels as well as eosinophil counts expression of IL-4, IL-13, IL-5, IL-6, IL-8, and vascular endo- were found positively correlated with serum IL-31 expression thelial growth factor (VEGF) in serum and nasal lavage of AR (P < 0.001, Figure 3e–g). Besides, serum VEGF expression children compared with control (P = 0.001, Figure 2a–l), espe- was positively correlated with IL-31 expression in asthma chil- cially in children with asthma. High expression of mucin 5AC dren (P < 0.001, Figure 3h). The serum IL-6, IL-8, and VEGF (MUC5AC) was only found in nasal lavage instead of serum in expression was positively correlated with neutrophil counts in AR children, especially in those children with asthma (P = 0.001, asthma children (P < 0.001, Figure 3i–k). Table 1. Demographic characteristics of AR children and normal controls Group AR group AR with asthma group Control Number 42 18 20 Sex (male:female) 22:20 10:8 12:8 Age (months) 75.7 ± 38.0 76.0 ± 34.8 73.0 ± 36.8 History of asthma, n (%) — 18 (100) — Family history of atopy, n (%) 20 (47.6)* 10 (55.5)* 2 (10) Exposure to smoking, n (%) 18 (42.3)* 11 (61.1)*,** 1 (5) Eosinophilsa (count/mm3) 132 (80–1420)* 172 (103–1630)*,** 84 (3–210) Neutrophilsa (count/mm3) 8,700 (3,000–15,300) 11,400 (8,000–18,600)*,** 7,700 (3,300–12,900) Basophilsa (count/mm3) 40 (10–140)* 38 (5–120)* 10 (3–15) Monocytesa (count/mm3) 256 (70–2,740) 289 (80–2,660) 242 (80–2,480) Lymphocytesa (count/mm3) 6,900 (3,100–16,400) 7,600 (2,900–17,100) 8,100 (2,000–14,300) ECPa (ng/ml) 34.2 (4.0–134.0)* 51.3 (24.0–168.0)*,** 10.9 (3.6–119.0) IgEa (IU/ml) 86.1 (2.5–1,600.0)* 109.3 (18.6–1,730.0)*,** 41.0 (7.3–87.0) AR, allergic rhinitis; ECP, eosinophil cationic protein; IgE, immunoglobulin E. aData presented as median values (minimum-maximum). *Compared with control group, P < 0.05. **Compared with AR group, P < 0.05. ab 0.0010 0.004 ** * 0.0008 * 0.003 0.0006 0.002 * 0.0004 in serum in nasal lavage 0.001 0.0002 Relative density of IL-31 mRNA Relative density of IL-31 mRNA 0.0000 0.000 ControlAR AR with asthma ControlAR AR with asthma cd * 300 ** 300 * ** 200 200 100 serum (pg/ml) 100 nasal lavage (pg/ml) IL-31 protein expression in IL-31 protein expression in 0 0 ControlAR AR with asthma ControlAR AR with asthma Figure 1. Serum and nasal interleukin (IL)-31 mRNA and protein expression levels in allergic rhinitis (AR) were significantly higher than those in the nor- mal ­controls, especially in those patients with asthma (a–d). (a) *P < 0.01, Con vs. AR; **P < 0.05, AR vs. AR with asthma. (b) *P < 0.01, Con vs. AR; *P < 0.01, AR vs. AR with asthma. (c) **P < 0.05, Con vs. AR; **P < 0.05, AR vs. AR with asthma. (d) *P < 0.01, Con vs. AR; *P < 0.01, AR vs. AR with asthma. Copyright © 2015 International Pediatric Research Foundation, Inc. Volume 77 | Number 1 | January 2015 Pediatric Research 21 Articles Liu et al. ab c 6 10 * 60 ** ** * 8 4 * * 40 6 * 4 20 2 serum (pg/ml) nasal lavage (pg/ml) nasal lavage (pg/ml) 2 IL-5 protein expression in IL-4 protein expression in IL-4 protein expression in 0 0 0 Control AR AR with asthma Control AR AR with asthma Control AR AR with asthma de f 100 250 400 ** * ** 80 200 300 60 150 * * * 200 40 100 serum (pg/ml) serum (pg/ml) 100 20 nasal lavage (pg/ml) 50 IL-6 protein expression in IL-6 protein expression in IL-5 protein expression in 0 0 0 Control AR AR with asthma Control AR AR with asthma Control AR AR with asthma gh i 5,000 6,000 * 150 ** ** ** 4,000 * 4,000 100 3,000 ** 2,000 serum (pg/ml) 2,000 50 nasal lavage (pg/ml) 1,000 nasal lavage (pg/ml) IL-8 protein expression in IL-8 protein expression in IL-13 protein expression in 0 0 0 Control AR AR with asthma Control AR AR with asthma Control AR AR with asthma j kl 400 800 800 ** ** * 300 600 600 ** ** * 200 400 400 serum (pg/ml) serum (pg/ml) VEGF protein in 100 200 VEGF protein in 200 nasal lavage (pg/ml) IL-13 protein expression in 0 0 0 Control AR AR with asthma Control AR AR with asthma Control AR AR with asthma m 150 * * 100 50 nasal lavage (pg/ml) MUC5AC protein expression in 0 Control AR AR with asthma Figure 2.
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