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Jimmunol.1800667.Full.Pdf Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease This information is current as Seiji Segawa, Yuya Kondo, Yuji Nakai, Akira Iizuka, of September 25, 2021. Shunta Kaneko, Masahiro Yokosawa, Kotona Furuyama, Hiroto Tsuboi, Daisuke Goto, Isao Matsumoto and Takayuki Sumida J Immunol published online 7 November 2018 http://www.jimmunol.org/content/early/2018/11/06/jimmun Downloaded from ol.1800667 Supplementary http://www.jimmunol.org/content/suppl/2018/11/06/jimmunol.180066 Material 7.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 7, 2018, doi:10.4049/jimmunol.1800667 The Journal of Immunology Placenta Specific 8 Suppresses IL-18 Production through Regulation of Autophagy and Is Associated with Adult Still Disease Seiji Segawa,* Yuya Kondo,* Yuji Nakai,† Akira Iizuka,* Shunta Kaneko,* Masahiro Yokosawa,* Kotona Furuyama,* Hiroto Tsuboi,* Daisuke Goto,* Isao Matsumoto,* and Takayuki Sumida* Adult Still disease (ASD) is a systemic disorder of unknown etiology characterized by high spiking fever, rash, and arthritis. The purpose of this study was to identify genes specifically associated with the active phase of the disease. In this study, we have reported that placenta specific 8 (PLAC8) was a newly specific gene involved in ASD. DNA microarray and validation analysis using human monocytes revealed that the expression of PLAC8 was significantly higher in active-ASD patients than in inactive-ASD patients Downloaded from and healthy controls. In ASD, PLAC8 expression level correlated with serum levels of CRP, ferritin, IL-1b, and IL-18. Stimulation of monocytes with LPS results in PLAC8 upregulation. LPS or nigericin stimulation of PLAC8-overexpressing human monocytic cell line (THP-1), but not mock THP-1 cells, was associated with a significant decrease in IL-1b and IL-18 production. PLAC8 overexpression in THP-1 cells was associated with enhanced autophagy and suppression of IL-1b and IL-18 production. There- fore, we found that PLAC8 was upregulated in activated monocytes, as was IL-1b and IL-18. The upregulated PLAC8 acts on the synthesis of inactive precursors of IL-1b and IL-18 and seemed to suppress the production of IL-1b and IL-18 by negative http://www.jimmunol.org/ feedback through enhanced autophagy, resulting in the suppression of ASD. The results highlight the role of PLAC8 in the pathogenesis of ASD and suggest its potential suitability as an activity marker and therapeutic target in ASD. The Journal of Immunology, 2018, 201: 000–000. dult Still disease (ASD) is a rare multisystemic auto- higher levels of IL-18 correlate with ASD activity (6, 8). Thus, inflammatory disorder of unknown etiology. The clinical IL-18 is thought to be one of the most important factors in the A features correlate with systemic manifestations, such as pathogenesis of ASD. However, there is little or no information on a high spiking fever, arthralgia or arthritis, and an evanescent the regulatory process involved in the production of IL-18 and by guest on September 25, 2021 salmon-pink maculopapular skin rash (1, 2). Although the path- other inflammatory cytokines in ASD. ogenesis of ASD is not clear, the interplay of viral infections, Activation of myeloid cells, including monocytes, macrophages, genetic factors, and immune dysregulation, including cytokine- dendritic cells, and neutrophils, is the hallmark of ASD. Especially, mediated inflammation and enhanced apoptosis, may contribute several markers and cytokines that reflect macrophage activation to the development of this disease (3). correlate with ASD activity (3). In contrast, activated monocytes Previous reports investigated the pathogenic roles of several are known to produce IL-6, TNF-a, IL-1b, and IL-18 through proinflammatory cytokines in ASD, including IL-1b, IL-6, IL-18, several stimuli including viral and bacterial components (9, 10). In TNF-a, and IFN-b (3). Among these cytokines, IL-18 is thought patients with ASD, uncontrolled activation of monocytes could to be the upstream initiator of the proinflammatory cytokine induce cytokine storms and several systemic disorders. However, cascades, and serum IL-18 levels are particularly elevated in the genes involved in the regulation of monocyte activation remain ASD, unlike in other inflammatory conditions (4–8). Furthermore, unidentified in ASD. Therefore, identification of specific genes in *Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan. E-mail Tsukuba, Ibaraki 305-8575, Japan; and †Institute for Food Sciences, University of address: [email protected] Hirosaki, Hirosaki 038-0012, Japan The online version of this article contains supplemental material. ORCIDs: 0000-0001-8863-5534 (S.K.); 0000-0001-6646-2003 (D.G.); 0000-0002- Abbreviations used in this article: ASD, adult Still disease; BCL2A1, BCL2-related 7995-9294 (I.M.). protein A1; CD55, CD55 molecule; CLU, clusterin; CRP, C-reactive protein; Received for publication May 11, 2018. Accepted for publication October 3, 2018. CYP1B1, cytochrome P450 family 1 subfamily B polypeptide 1; FARMS, Factor Analysis for Robust Microarray Summarization; FCGR1B, Fc fragment of IgG high This work was supported by Research Program for Intractable Diseases, Health and affinity Ib; GO, Gene Ontology; HC, healthy control; IL1RN, IL-1 receptor antago- Labor Sciences research grants from the Ministry of Health, Labor and Welfare, nist; ISD, immunosuppressive drug; 3-MA, 3-methyladenine; MBL, Medical and Japan, and the Ministry of Education, Culture, Sports, Science and Technology. Biological Laboratories; mSAM, modified SAM; PCA, principal component analy- S.S. and T.S. designed the study. S.S., Y.K., A.I., S.K., M.Y., K.F., D.G., and I.M. sis; PIM1, Pim-1 proto-oncogene; PLAC8, placenta specific 8; PLAC8–THP-1, performed analysis and collected the data. Y.K. and H.T. oversaw patient recruitment. PLAC8-overexpressing THP-1; PLSCR1, phospholipid scramblase 1; PM/DM, poly- Y.N. performed DNA microarray analysis. S.S. analyzed the data and wrote the myositis/dermatomyositis; qPCR, quantitative PCR; RA, rheumatoid arthritis; manuscript. All authors have read and approved the manuscript for publication. S100A12, S100 calcium binding protein A12; SAM, Significance Analysis of Micro- arrays; SLE, systemic lupus erythematosus; SOD2, superoxide dismutase 2; SS, The microarray data presented in this article have been submitted to the Gene Sjo¨gren syndrome; STEAP4, STEAP family member 4. Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE113645. Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 Address correspondence and reprint requests to Prof. Takayuki Sumida, Division of Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800667 2 ROLE OF PLAC8 IN ASD monocytes could help in the assessment of disease activity and (24) using the statistical language R (http://www.r-project.org/) (25) and severity and could be useful as therapeutic targets in ASD. Bioconductor (http://www.bioconductor.org/) (26). Global gene expression The present study was designed to clarify the specific genes in- profiles of all samples were evaluated with principal component analysis (PCA) (27) using the promp() function in R. To compare the genes up- volved in the progression of ASD. Using DNA microarray analysis, regulated in active ASD relative to inactive ASD, the Significance Analysis we identified placenta specific 8 (PLAC8) mRNA to be significantly of Microarrays (SAM) (28) was applied to the FARMS-normalized paired upregulated in monocytes from patients with active ASD. PLAC8 is data with modification. In brief, considering the dynamic range of changes a small protein known to be highly expressed in giant trophoblasts in gene expression, using the weight term of the weighted average dif- ference (29) statistic, the modified SAM (mSAM) statistic for the ith probe and the spongiotrophoblast layer of the mouse placenta (11, 12). In set, mSAM(i), is calculated simply as humans, PLAC8 is expressed in dendritic cells, myeloid cells, lymphoid cells, and epithelial cells in lungs and intestines (13, 14). mSAMðÞ¼i SAMi wi; Multiple functions of PLAC8 have been demonstrated in the im- mune system, such as adipocyte differentiation, infectious disease, where wi is relative average log signal intensity of the ith probe set diabetes, cancers, and autophagy (14–18). However, little is known (i.e., weight). Then we rank the probe sets according to the mSAM statistic,
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