Cellular Immunology 290 (2014) 116–119

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Interleukin-28A promotes IFN-c production by peripheral blood mononuclear cells from patients with Behçet’s disease Bing Li, Chufang Xie, Xiaomin Lin, Shao Bo Su ⇑ The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

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Article history: Received 12 February 2014 Accepted 10 June 2014 Available online 18 June 2014 Keywords: IL-28A Behçet’s disease Cytokine PBMCs

a b s t r a c t Behçet’s disease (BD) is an autoimmune disease of unknown etiology. Interleukin-28A (IL-28A) promotes immune responses and may participate in the pathogenesis of autoimmune diseases. To examine the role of IL-28A in the pathogenesis of BD, we measured the expression of IFN-c and IL-17 by IL-28A-stimulated peripheral blood mononuclear cells (PBMCs) from 19 patients with BD and 16 healthy individuals. We found that IFN-c and IL-17 were undetectable in the sera from BD patients and control subjects. The mRNA expression and protein production of IFN-c by IL-28A-stimulated PBMCs from BD patients were significantly increased compared to healthy individuals. No significant difference was observed in the mRNA expression and protein production of IL-17 by IL-28A-stimulated PBMCs between BD patients and normal individuals. Ó 2014 Published by Elsevier Inc.

1. Introduction Three highly related cytokines IL-28A (IFN-k2), IL-28B (IFN-k3) and IL-29 (IFN-k1) were discovered in 2003. These cytokines signal through a heterodimeric receptor consisting of IL-28Ra (IFN-lR1 or CRF2-12) responsible for ligand specificity and IL-10Rb (IL-10R2 or CRF2-4) shared with all other IL-10 family members [1–3]. The potent antiviral and anti-cancer activities of IFN-ks are well established [4–6]. More recently, immunoregulatory functions of IFN-ks have also been suggested. These activities include increasing NK and T cell cytotoxicity [6], upregulating MHC class I molecule expression on tumor cells to promote antigen presentation [1,2] and mediating cell apoptosis [7–9]. More interestingly, transgenic expression of IL-28A in vivo promotes the induction of Th1 responses and the severity of Concanavalin (ConA)-induced liver injury [10]. These data suggest that IL-28A functions as a key mediator in immune responses. Behçet’s disease (BD) is a chronic systemic inflammatory autoimmune disease of unknown etiology. It is characterized by recurrent episodes of oral and genital ulcers, uveitis, and cutaneous, vascular, and neurological involvement [11,12]. It is one of the most common forms of uveitis in China and Japan [13]. A number of clinical and laboratory findings suggest a strong polarized

⇑ Corresponding author. Address: The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 S Xianlie Road, Guangzhou 510060, China. E-mail address: [email protected] (S.B. Su). http://dx.doi.org/10.1016/j.cellimm.2014.06.003 0008-8749/Ó 2014 Published by Elsevier Inc.

Th1 and Th17 immune response in BD and in experimental autoimmune uveoretinitis (EAU), a model of human uveitis induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP) [14–18]. As yet, it is not clear whether IL-28A is involved in BD development. In view of the role of IL-28A in autoimmune diseases, the present study was designed to examine the capacity of IL-28A to induce the production of IFN-c and IL-17 by peripheral blood mononuclear cells (PBMCs) from BD patients. 2. Materials and methods 2.1. Patients Nineteen BD patients with active uveitis (10 men and 9 women; mean age, 41 years; range, 20–56 years) referred to Zhongshan Ophthalmic Center, Sun Yat-sen University in Guangzhou, PR China, were included in this study. The diagnosis of Behçet’s disease was based on the criteria designed by the International Study Group for Behçet’s disease [19]. All patients, referred from various provinces throughout China, showed a recurrent intraocular inflammation (active uveitis stage). These patients had been intermittently treated with corticosteroids but had received no immunosuppressive agents before visiting our ophthalmic center. The history of uveitis in these patients ranged from 15 to 90 months. The common ocular findings in the patients were non-granulomatous anterior uveitis (82%), retinal vasculitis (97%) and retinitis (100%). The common extraocular manifestations were recurrent

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aphthous stomatitis (100%), multiform skin lesions (85%), recurrent genital ulcers (60%) and arthritis (56%). Blood samples were obtained from these patients before cyclosporine or chlorambucil treatment. Sixteen healthy individuals (9 men and 7 women; mean age, 38 years; range, 24–53 years) served as controls. All procedures followed the tenets of the Declaration of Helsinki, and informed consent was obtained from all patients and normal control subjects. 2.2. PBMC isolation and culture Heparinized blood samples (10 ml) were obtained from BD patients and healthy individuals. Isolation of PBMCs was performed by density gradient centrifugation with Ficoll-Paque. The PBMCs obtained from each sample were divided into four aliquots and cultured in 24-well tissue culture plates as follows: Group 1: 2  106 PBMCs + medium; Group 2: 2  106 PBMCs + 20 ng/ml IL-28A; Group 3: 2  106 PBMCs + 5 lg/ml PHA (phtohemagglutinin A); Group 4: 2  106 PBMCs + 5 lg/ml PHA + 20 ng/ml IL-28A. Recombinant human IL-28A was from R&D Systems (MN, USA), PHA was from Sigma (MO, USA). These cells were cultured in RPMI1640 for 72 h at 37 °C in an atmosphere containing 5% CO2. The cultured cells and supernatants were collected and analyzed for IFN-c and IL-17 expression by quantitative real-time PCR and ELISA, respectively. 2.3. RNA preparation and quantitative real-time PCR (qRT-PCR) 6

Total RNA was extracted from PBMCs (2  10 cells) isolated from each group using the TRIzol reagent (Gibco Life Technologies, CA, USA) according to the manufacturer’s instructions. The cDNA template for analysis of gene expression was prepared by reverse transcription of RNA using the PrimeScript RT Master Mix perfect real-time kit (Takara Biotechnology, DaLian, China). Quantitative real-time PCR was performed using an ABI PRISM 7000 (Applied Biosystems Inc., CA, USA), and the gene expression was analyzed by Platinum SYBR Green qPCR SuperMix-UDG (Invitrogen by Life Technologies, CA, USA). PCR amplification was performed in triplicate, and water was used to replace cDNA as a negative control. The reaction protocol involved preincubation at 50 °C for 2 min (for incubation of UDG) and 95 °C for 2 min, followed by 40 amplification cycles comprising 95 °C for 15 s and annealing for 30 s at 60 °C. The results were normalized with the housekeeping gene human-GAPDH. The primer sequences were as follows: GAPDH-F: GGTATCGTGGAAGGACTCATGAC; GAPDH-R: ATGCCAGTGAGCTTCCCGTTCAGC; IFN-c-F: CTTTAAAGATGACCAGA GCATCCAA; IFN-c-R: GGCGACAGTTCAGCCATCAC; IL-17-F: CTGAA CATCCATAACCGGAATACCA; IL-17-R: AGCGTTGATGCAGCCCAAG.

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3. Results 3.1. Levels of IFN-c, Il-4 and IL-17 in the sera from BD patients and control subjects The levels of IFN-c, IL-4 and IL-17 in the sera from BD patients and control subjects were measured by ELISA. The sensitivity detection of IFN-c, IL-17, and IL-4 was 15.625 pg/ml, 15.625 pg/ ml and 31.25 pg/ml, respectively. The levels of IFN-c, IL-4 and IL-17 in the sera were undetectable (data not shown). 3.2. The effects of IL-28A on the expression of IFN-c and IL-17 mRNA by PBMCs from BD patients and normal subjects The levels of IFN-c and IL-17 mRNA in PBMCs from BD patients and normal subjects were determined by qRT-PCR. A polyclonal stimulant PHA, increased the expression of IFN-c mRNA by PBMCs from both BD patients and normal subjects, was with higher level increase shown by PBMCs from BD patients. IL-28A markedly increased the expression of IFN-c mRNA by PBMCs from BD patients (13.8-fold compared with untreated PBMCs) in the presence of PHA (Fig. 1A). IL-28A did not show any effect on IL-17 mRNA production by PHA-stimulated PBMCs (Fig. 1B). 3.3. The effects of IL-28A on the production of IFN-c by PBMCs from BD patients and normal controls IFN-c was undetectable in the sera of both BD patients and normal control subjects. A low concentration of IFN-c (30.65 pg/ml)

2.4. Cytokine assays Levels of IFN-c and IL-17 in serum and culture supernatants were assayed by ELISA. Procedures were performed according to the manufacturer’s instructions provided with each DuoSet ELISA Development System (R&D systems, MN, USA). The serum samples were two fold dilutions with 1% BSA-PBS. The sensitivity detection of IFN-c, IL-17, and IL-4 was 15.625 pg/ml, 15.625 pg/ml and 31.25 pg/ml, respectively. 2.5. Statistical analysis Data are expressed as means ± SDs. Statistical analysis was performed using Student t-test. A level of P < 0.05 was considered to be statistically significant.

Fig. 1. IFN-c and IL-17 gene expression by PBMCs from BD patients (n = 19) and control subjects (n = 16). (A) IFN-c gene expression in PBMCs. (B) IL-17 gene expression by PBMCs. PBMCs from BD patients and control subjects were incubated with 20 ng/ml IL-28A for 72 h. The levels of IFN-c and IL-17 mRNA were determined by quantitative reverse transcription-PCR. The group which cells were treated with medium only was used as control. All mRNA values were normalized against the levels of human GAPDH mRNA. The normalized value derived from control group was designated as 1 and the normalized values of treatment groups are expressed as fold increase over the control group. Data are expressed as means ± SDs. PCR was performed with triplicate samples and all experiments were repeated three times.

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showed increased production of IFN-c protein in response to IL28A. The results showed that IL-28A significantly augmented the production of IFN-c. The stimulatory effect of IL-28Awas more pronounced on PBMCs from BD patients (856.32 pg/ml) than on cells from control subjects (471.86 pg/ml) (Fig. 2B). 3.4. The effects of IL-28A on the production of IL-17 by PBMCs from BD patients and control subjects IL-17 was below the detection level in the serum and low level in the supernatants of IL-28A-stimulated PBMCs from both BD patients and normal subjects (Fig. 3A). PHA stimulated the production of IL-17 in PBMCs from BD patients and control subjects with higher levels in BD patients (470.23 pg/ml) than in control subjects (221.38 pg/ml) (P < 0.001). IL-28A did not further increase IL-17 production by PHA-stimulated PBMCs from BD patients. IL-28A did not have any effect on IL-17 protein production by PHA-stimulated PBMCs (Fig. 3B). 4. Discussion

Fig. 2. IFN-c production by PBMCs from BD patients. PBMCs were cultured with PHA in the presence and absence of 20 ng/ml IL-28A for 72 h. IFN-c produced by PBMCs from BD patients (n = 19) and control subjects (n = 16) was measured by ELISA. Data are expressed as the means ± SDs.

was detected in the supernatants of PBMCs from BD patients stimulated by rIL-28A alone (Fig. 2A). IFN-c was undetectable in the supernatants of normal control PBMCs stimulated by IL-28A alone. PBMCs from BD patients and normal subjects activated with PHA

Fig. 3. L-17 production by PBMCs from BD patients. PBMCs were cultured with PHA in the presence and absence of 20 ng/ml IL-28A for 72 h. IL-17 produced by PBMCs from BD patients (n = 19) and control subjects (n = 16) was measured by ELISA. Data were expressed as the means ± SDs.

Although the potent antiviral and antitumor functions of IL-28A are well established [20–22], less attention has been paid to the activities of IL-28A on PBMCs from patients. In the present study, we found that IL-28A significantly increased the expression of IFN-c at both the mRNA and protein levels by PHA-stimulated PBMCs from BD patients compared with PBMCs from control subjects. These results suggest that BD patient PBMCs are highly sensitive to IL-28A which may promote Th1 responses and play a role in the development of BD. To our knowledge, this study is the first demonstration of the immunoregulatory function of IL-28A in BD patients. Our results are consistent with findings in mouse disease models. For instance, IL-28A-transgenic mice showed a marked augmentation of ConA-induced hepatitis with upregulated IFN-c production [6]. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease by upregulating the expression of IFN-c [23]. These observations indicate that while IL-28A acts as a causative agent in Th1mediated diseases it also shows a potential therapeutic benefit for Th2-type diseases. Numerous studies have indicated that Th17 cells and their signature cytokine IL-17 are critical for immune responses [24]. Th1 and Th17 cells are effector cells involved in the pathogenesis of BD [14–18]. However, our data in this study showed that IL-28A did not increase the expression of IL-17 by PHA-stimulated PBMCs from BD patients. Therefore, IL-28A may inhibit IL-17 expression and enhance Th1 responses to mediate Behçet’s disease. Consistent with this, Koltsida et al. showed that IL-28A suppressed experimental allergic asthma by inhibiting Th2 and Th17 responses [23]. It is interesting to note that our results of IL-17 expression in BD patients seem to be in conflict with the observation in the EAU animal model. EAU elicited by IRBP immunization is a model for human uveitis. Evidence from human and animals revealed the roles of both Th1 and Th17 cells in the initiation of this autoimmune disease [15,25]. In EAU model with B10RIII mice, a marked upregulation of IFN-c and IL-17 is observed following IL-28A treatment in vivo (manuscript submitted for publication). The different effect of IL28A on Th17 responses in asthma versus EAU may be due to differences in mouse strains used that exhibited variable cytokine profiles in response to IL-28A. It is likely that B10.RIII mice produce more IFN-c and IL-17 in response to Il-28A that exacerbate the induction of EAU. Furthermore, the pathogenesis of human autoimmune uveitis, such as BD, involves other organs, suggesting that BD may be part of a systemic autoimmune syndrome. In contrast, EAU affects only the eyes with an immune

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privilege, thus suggesting a difference in the etiology of the mouse and human forms of diseases. IL-28R1 is a specific cell receptor for IL-28A and is expressed by various immune cells in human and mouse, including monocytes, T-cells, B-cells, and NK-cells [26,27]. The sensitivity of these cells to Type III IFNs may vary due to the presence of a secreted single-chain receptor that binds IFN-k and acts as a negative regulator [26]. Our results showed that IL-28A increased IFN-c expression by PHA-stimulated PBMCs from BD patients thus support the notion that IL-28A has a direct effect on PBMCs. Our results are consistent with the studies of the effects of IL-28/29 on monocytes, DCs and T-cells [10,28–31] in which IL-28/29 reduces the polarization of human CD4+ Th2 cells and alters Th1/Th2 balance by inhibiting the production of IL-13 but enhancing the production of IFN-c by T cells in vitro [30,32]. IL-28/29 shuts down Th2 polarization pathways therefore may enhance Th1 responses [33]. In asthma patients, IL-28/29 production by bronchial epithelial cells was deficient resulting in severe airway inflammation and increased virus load [34]. Thus, IL-28A/29 has shown important regulatory activities in orchestrating the pathogenesis of autoimmune diseases. In conclusion, in this study, we found that the mRNA expression and protein production of IFN-c by IL-28A-stimulated PBMCs from BD patients were significantly increased compared to healthy individuals. No significant difference was observed in the mRNA expression and protein production of IL-17 by IL-28A-stimulated PBMCs between BD patients and normal individuals. Our study provides evidence for potential IL-28A participation in BD and its value as a therapeutic agent. 5. Contributors B.L., C.X., X.L. and S.B.S. made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data. B.L. and S.B.S. were in drafting the article and revising it critically for important intellectual content and final approval of the version to be published. 6. Ethics approval Ethics committee at Zhongshan Ophthalmic Center, Sun Yat-sen University, China. Acknowledgments We are grateful to Hongyan Zhou and Xiangkun Huang for their technical assistance. This work was supported by grants from the Science and Technology Planning Project of Guangdong Province, China (2009B030801170), and the Fundamental Research Funds of State Key Laboratory of Ophthalmology (303060202400439). References [1] S.V. Kotenko, G. Gallagher, V.V. Baurin, A. Lewis-Antes, M. Shen, N.K. Shah, et al., IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex, Nat. Immunol. 4 (2003) 69. [2] P. Sheppard, W. Kindsvogel, W. Xu, K. Henderson, S. Schlutsmeyer, T.E. Whitmore, et al., IL-28, IL-29 and their class II cytokine receptor IL-28R, Nat. Immunol. 4 (2003) 63. [3] J. Siren, J. Pirhonen, I. Julkunen, S. Matikainen, IFN-alpha regulates TLRdependent gene expression of IFN-alpha, IFN-beta, IL-28, and IL-29, J. Immunol. 174 (2005) 1932. [4] M.D. Robek, B.S. Boyd, F.V. Chisari, Lambda interferon inhibits hepatitis B and C virus replication, J. Virol. 79 (2005) 3851. [5] N. Ank, M.B. Iversen, C. Bartholdy, P. Staeheli, R. Hartmann, U.B. Jensen, et al., An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity, J. Immunol. 180 (2008) 2474. [6] M. Numasaki, M. Tagawa, F. Iwata, T. Suzuki, A. Nakamura, M. Okada, et al., IL28 elicits antitumor responses against murine fibrosarcoma, J. Immunol. 178 (2007) 5086.

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Interleukin-28A promotes IFN-γ production by peripheral blood mononuclear cells from patients with Behçet's disease.

Behçet's disease (BD) is an autoimmune disease of unknown etiology. Interleukin-28A (IL-28A) promotes immune responses and may participate in the path...
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