Acta Dermato-Venereologica 97-10CompleteContent | Page 12

1172 INVESTIGATIVE REPORT Increased Interleukin-19 Expression in Cutaneous T-cell Lymphoma and Atopic Dermatitis Tomonori OKA, Makoto SUGAYA, Naomi TAKAHASHI, Rina NAKAJIMA, Sayaka OTOBE, Miyoko KABASAWA, Hiraku SUGA, Tomomitsu MIYAGAKI, Yoshihide ASANO and Shinichi SATO Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan Interleukin-19 (IL-19), a pro-inflammatory cytokine known to stimulate the production of T helper type 2 (Th2) cytokines, is induced by IL-17A and highly ex- pressed in the lesional skin of psoriasis and atopic der- matitis (AD). This aim of this study was to investigate whether IL-19 is involved in cutaneous T-cell lym­ phoma (CTCL) and AD. IL-19 levels were significantly higher in the sera of patients with AD and those with advanced-stage CTCL than in normal controls, corre- lating significantly with clinical disease markers. IL- 19 mRNA levels in lesional skin of both diseases were significantly elevated. Immunohistochemical staining revealed that IL-19 was expressed in the epidermis of AD skin and CTCL skin. In vitro, IL-17A and IL-4 in- creased IL-19 mRNA expression in human keratino- cytes. Thus, IL-19 was increased in the sera and skin of AD and CTCL. These results suggest that IL-19 is important for bridging Th17 to Th2 in these diseases. Key words: IL-19; atopic dermatitis; cutaneous T-cell lympho- ma; keratinocytes; IL-4; IL-17A. Accepted Jun 8, 2017; Epub ahead of print Jun 9, 2017 Acta Derm Venereol 2017; 97: 1172–1177. Corr: Makoto Sugaya, Department of Dermatology, the University of To- kyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113- 8655, Japan. E-mail: [email protected] I nterleukin (IL)-19 is a member of the so-called IL-10 family of cytokines. IL-19 was discovered in 2000 by means of a bioinformatics search for IL-10-related molecules (1). Important cellular sources of IL-19 are thought to be monocytes (1–3), keratinocytes (4–8) and bronchial epithelial cells (9). IL-4 and IL-17A have been reported to induce IL-19 expression by human keratinocytes (4, 5, 7, 8). The IL-19 receptor consists of IL-20R1 and IL-20R2 (10–12). The IL-19 subfamily has 3 members, IL-19, IL-20 and IL-24, which have a very similar tertiary structure (13) and are able to bind to and signal through IL-20R1 and IL-20R2. Keratinocytes express these receptors, suggesting that IL-19 can act in an autocrine manner (8). Many groups have documented increased IL-19 ex- pression in the diseased skin of psoriasis in comparison with non-diseased skin of the same patients or that of healthy controls (4, 5, 14–16). IL-19 is also reported to be up-regulated in lesional skin of atopic dermatitis (AD) (4, 5). AD is a chronic inflammatory skin disease that affects 10–20% of children and 1–3% of adults in doi: 10.2340/00015555-2723 Acta Derm Venereol 2017; 97: 1172–1177 developed countries. It is well known that T helper type 2 (Th2) cells, expressing IL-4, IL-5, and IL-13, play an essential role in the pathophysiology of AD (17). IL-19 has been demonstrated to increase Th2 cytokine expression in activated T cells (3, 18). Serum IL-19 levels are elevated in patients with asthma, suggesting an essential role in the pathogenesis of asthma (18), which is another Th2 cell-mediated disease. Serum IL- 19 levels in patients with AD, however, have not been investigated previously. Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-trafficking T cells. Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of CTCL. Prior studies have shown increased levels of Th2 cytokines and Th2-associated genes in T cells from patients with CTCL (19). Although up-regulated IL-19 in breast cancer has been shown to promote tumour progression (20), little is known about an association between IL-19 and other malignancies. IL-19 has not been investigated for possible involvement in CTCL. The aim of this study was therefore to examine serum IL-19 levels and IL-19 expression in lesional skin of AD and CTCL. A further aim was to investigate which cytokines would induce IL-19 expression by normal human keratinocytes. MATERIALS AND METHODS Tissue and serum samples Messenger RNA (mRNA) was obtained from biopsy materials of lesional skin of MF/SS (n = 17: patch MF 4, plaque MF 3, t umour MF 5, erythrodermic MF 2, SS 3; mean  ±  standard deviation (SD) age: 57.6  ±  12.7 years; 12 males and 5 females), AD (n = 7; mean  ±  SD age: 36.3  ±  16.0 years; 5 males and 2 females), and normal skin adjacent to benign skin tumours (n = 8; mean  ±  SD age: 49.1  ±  21.0 years; 4 males and 4 females) using RNeasy Fi- brous Tissue Mini Kit (QIAGEN, Valencia, CA, USA). Samples for immunohistochemistry were lesional skin of MF/SS (n = 10: patch MF 2, plaque MF 3, tumour MF 3, SS 2) or AD (n = 10), and normal skin adjacent to benign skin tumours (n = 10). Serum samples were obtained from 28 patients with MF/SS (patch MF 7, plaque MF 10, tumour MF 9, erythrodermic MF 1, SS 1; mean  ±  SD age: 54.5  ±  18.1 years; 15 males and 13 females), 35 patients with AD (10 mild cases, 10 moderate cases, and 15 severe cases; mean  ±  SD age: 30.8  ±  12.0 years; 23 males and 12 females), and 17 healthy control subjects (mean  ±  SD age: 47.6  ±  20.6 years; 11 males and 6 females). The healthy controls had no history of al- lergy, AD, psoriasis, or CTCL. All samples were collected during daily clinical practice in the University of Tokyo Hospital. The medical ethics committee of the University of Tokyo approved This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2017 Acta Dermato-Venereologica.