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Role of Mir-146A in the Regulation of Inflammation in an in Vitro Model Of Biochemistry and Molecular Biology Role of miR-146a in the Regulation of Inflammation in an In Vitro Model of Graves’ Orbitopathy Sun Young Jang,1,2 Min Kyung Chae,3 Joon H. Lee,4 Eun Jig Lee,5 and Jin Sook Yoon3 1Department of Ophthalmology, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea 2Department of Medicine, Yonsei University Graduate School of Medicine, Seoul 3Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea 4Myung-Gok Eye Research Institute at Kim’s Eye Hospital, Konyang University College of Medicine, Nonsan, Korea 5Department of Endocrinology, Severance Hospital, Institue of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea Correspondence: Jin Sook Yoon, PURPOSE. To investigate the role of microRNA 146a (miR-146a) in the regulation of Institute of Vision Research, Depart- inflammation in an in vitro model of Graves’ orbitopathy (GO). ment of Ophthalmology, Yonsei Uni- versity College of Medicine, 50 METHODS. The level of miR-146a expression in orbital adipose tissue was compared between Yonsei-ro, Seodaemun-ku, 03722 GO and non-GO by quantitative real-time PCR (qPCR). The effects of interleukin 1b (IL-1b)on Seoul, Korea; miR-146a expression were analyzed in orbital fibroblasts by qPCR. To investigate the [email protected]. molecular mechanism underlying IL-1b–induced miR-146a expression, the effects of Submitted: January 25, 2016 inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB), mitogen- Accepted: June 25, 2016 activated protein kinase/extracellular signal–regulated kinases (MEK)-1/2, c-Jun N-terminal kinases (JNK)-1/2, p38 MAP kinase, and phosphatidylinositol-4,5-bisphosphate 3-kinase Citation: Jang SY, Chae MK, Lee JH, Lee EJ, Yoon JS. Role of miR-146a in (PI3K) were analyzed. The effects of miR-146a mimics and inhibitors on IL-1b–induced IL-6 the regulation of inflammation in an in release were examined by ELISA and Western blotting. vitro model of Graves’ orbitopathy. RESULTS. The level of miR-146a expression was significantly higher in GO orbital adipose tissue Invest Ophthalmol Vis Sci. than in non-GO (P ¼ 0.032). Interleukin 1b induced a time- and concentration-dependent 2016;57:4027–4034. DOI:10.1167/ increase in miR-146a expression. Interleukin 1b (10ng/mL,16hours)inducedan iovs.16-19213 approximately 17.5-fold increase in miR-146 expression. The increase in miR-146a expression by IL-1b was significantly inhibited by NF-jB, JNK-1/2, and PI3K inhibitors (1.94 6 0.25, 5.28 6 0.34 and 9.73 6 2.32-fold, respectively, P < 0.05 compared with IL-1b–induced miR- 146 expression, independent t-test). Interleukin 1b–induced IL-6 protein production was further decreased by miR-146a mimics, but not by inhibitors of miR-146a. CONCLUSIONS. MicroRNA 146a was upregulated by inflammatory stress in orbital fibroblasts. Our results indicated that miR-146a had a positive effect on the anti-inflammatory process. MicroRNA 146a may play a role in the regulation of inflammation in orbital fibroblasts, and may participate in the pathogenesis of GO. Keywords: miR-146a, inflammation, Graves’ orbitopathy raves’ orbitopathy (GO) is an inflammatory autoimmune important regulatory roles by targeting mRNAs for cleavage or G disorder of the orbit. Previous studies have indicated that translational repression.8–10 Thus, they negatively regulate gene the thyroid stimulating hormone (TSH) receptor, which is expression at the posttranscriptional level. Several recent expressed on orbital fibroblasts, is the autoimmune target of studies have shown that inflammatory autoimmune diseases, GO.1–4 Binding of autoantibodies to TSH receptors, expressed such as rheumatoid arthritis (RA),11 systemic lupus erythema- on orbital fibroblasts, activates the T cell–dependent inflam- tosus (SLE),12,13 ulcerative colitis,14 and psoriasis15 have been matory process. Thus, GO is believed to be related to T cell– reported to be associated with altered miRNA expression. Thus, mediated autoimmunity to an antigen present in orbital based on reports that inflammatory autoimmune conditions are fibroblasts. Activated CD4þ T cells secrete IL-1, IFN-c, and related to altered miRNA expression, we postulated that TNF-a, inducing the expression of TSH receptor and CD40 on specific miRNAs may also be associated with GO. the surface of orbital fibroblasts, which promote the secretion Located in the LOC285628 gene on human chromosome 5, of IL-6, À8, fibronectin, type 1 collagen, and glycosaminogly- miRNA 146a (miR-146) is a relatively well known miRNA in cans.5–7 Interaction with CD4þ T cells enhances orbital inflammatory autoimmune diseases.10,16 Studies have indicated fibroblast activation, proliferation, differentiation, and lipid that miR-146a plays an important role in the pathogenesis of accumulation. several autoimmune disorders, such as RA,11,17 SLE,13 osteoar- MicroRNAs (miRNAs) are endogenous, single-stranded, thritis (OA),18 and Sj¨ogren syndrome.19 MicroRNA 146a seems noncoding RNAs, 18 to 24 nucleotides in length that can play to act through inhibition of the nuclear factor kappa-light-chain- iovs.arvojournals.org j ISSN: 1552-5783 4027 This work is licensed under a Creative Commons Attribution 4.0 International License. Downloaded from iovs.arvojournals.org on 09/28/2021 Role of miR-146a in Graves’ Orbitopathy IOVS j August 2016 j Vol. 57 j No. 10 j 4028 enhancer of activated B cell (NF-jB) pathway by downregula- The data were processed based on the quantile normalization tion of its target genes, such as TNF receptor–associated factor method using commercial software (GeneSpring GX 13.1; 6 (TRAF6) and IL-1 receptor–associated kinase 1 (IRAK1).20 Agilent Technologies). This normalization method aims to This leads to termination or mitigation of an inflammatory achieve a consistent distribution of intensities for each of a set response. Based on this background, we focused on miR-146a of arrays. The normalized and log-transformed intensity values in an inflammatory cellular model of orbital fibroblast were then analyzed using commercial software (Agilent inflammation induced by IL-1b. Technologies). The fold changes in the miRNA expression In this study, we first compare the expression levels of miR- between the GO and non-GO samples were calculated from 146a in orbital adipose tissue between GO and non-GO. Then, the signal values. MicroRNA expression was considered we determine the role of miR-146a in the regulation of significantly different if the fold change exceeded 1.5. Target inflammation in an in vitro model of GO. prediction was performed using a cutoff at the 95% percentile using the TargetScan6.2 database in the public domain (http:// www.targetscan.org/). METHODS Measurement of miR-146a Expression by Subjects and Cell Culture Protocol Quantitative Real-Time PCR Orbital adipose/connective tissue explants were obtained For quantitative real-time PCR (qPCR), the total RNA (1 g) of from 19 GO patients and from 17 age- and sex-matched l each orbital adipose/connective tissue sample obtained from control subjects with no history of GO. All GO patients another five GO patients and five non-GO normal controls was underwent orbital decompression for proptosis correction isolated using a miRNA isolation kit (mirVana; Ambion, Austin, and control subjects underwent cosmetic upper and lower TX, USA), and reverse-transcribed into complementary DNA blepharoplasty. Informed written consent was obtained from using a microRNA reverse transcription kit (TaqMan; Applied all subjects and this study was approved by the Institutional Biosystems, Carlsbad, CA, USA). The resulting cDNA was Review Board of Severance Hospital, Yonsei University amplified using a thermocycler (ABI StepOnePlus Real Time College of Medicine. All GO patients were euthyroid status PCR; Applied Biosystems) with a universal PCR master mix at the time of surgery and had not been treated with steroids (TaqMan No AmpErase UNG; Applied Biosystems) and the or radiation therapy for at least 3 months. recommended PCR conditions for quantitative assessment of Orbital fibroblast cell cultures were performed according to 21–23 gene transcript levels in the tissue samples. All PCRs were the methods described previously. Briefly, for primary cell performed in triplicate. The catalog number of the primers cultures, tissue explants were minced and placed in plastic used was 000468 for miR-146a. RNU6B expression was used culture dishes containing Dulbecco’s modified Eagle’s medium for normalization, and the results were expressed as relative (DMEM):F12 (1:1) (Lonza, Basel, Switzerland), 20% fetal bovine fold changes of threshold cycle (Ct) value relative to the serum (FBS; Life Technologies, Carlsbad, CA, USA), and control group using the 2–DDCt method.24 penicillin–streptomycin (Life Technologies). After orbital fibro- blasts had grown out from the explants, monolayers were passaged serially by gentle treatment with trypsin/EDTA, and Cell Stimulation cells were incubated in DMEM with 10% FBS and antibiotics. Orbital fibroblasts were plated onto 6-well plates for assess- Cell cultures were grown in a humidified 5% CO2 incubator at ment of cytokine release and RNA extraction. Cells were 378C. Cells were stored in liquid N2 until needed and used stimulated in triplicate in DMEM:F12 with the indicated IL-1b between the third and seventh passage. (R&D Systems, Minneapolis, MN, USA) concentration (0, 1, 5, 10, and 20 ng/mL) or with 10 ng/mL of IL-1b for the indicated Microarray Analysis time (0, 3, 6, 16, and 24 hours). To assess the molecular mechanism of IL-1b–induced miR- For the microarray analysis, the total RNA in each orbital 146a expression, the effects of inhibitors of MEK-1/2, JNK-1/2, adipose/connective tissue sample obtained from eight GO p38 MAP kinase, and PI3-K were investigated using GO orbital patients and six non-GO normal controls was extracted fibroblasts.
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