title: Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses.
abstract: Multipotent human mesenchymal stromal cells (hMSCs) harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A)-secreting T (Th17) lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25--also known as IL--17E-as well as programmed death ligand-1 (PD-L1), a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.
authors: Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 35053, Taiwan.
authors: Wei-Bei
authors: WB
authors: Wang
authors: Department of Obstetrics/Gynecology, National Taiwan University Hospital and School of Medicine, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Men-Luh
authors: ML
authors: Yen
authors: National Institute of Cancer Research, NHRI, Tainan 70403, Taiwan; Taipei Medical University, Taipei 10031, Taiwan. Electronic address: kojiunn@nhri.org.tw.
authors: Ko-Jiunn
authors: KJ
authors: Liu
authors: Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 35053, Taiwan.
authors: Pei-Ju
authors: PJ
authors: Hsu
authors: Graduate Institute of Immunology, National Defense Medical Center, Taipei 11490, Taiwan.
authors: Ming-Hong
authors: MH
authors: Lin
authors: Department of Obstetrics/Gynecology, National Taiwan University Hospital and School of Medicine, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Pei-Min
authors: PM
authors: Chen
authors: Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors: Putty-Reddy
authors: PR
authors: Sudhir
authors: Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors: Chein-Hung
authors: CH
authors: Chen
authors: Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan.
authors: Chung-Hsuan
authors: CH
authors: Chen
authors: Graduate Institute of Immunology, National Defense Medical Center, Taipei 11490, Taiwan.
authors: Huei-Kang
authors: HK
authors: Sytwu
authors: Regenerative Medicine Research Group, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Zhunan 35053, Taiwan; Department of Obstetrics/Gynecology, Cathay General Hospital Shiji, Taipei 21174, Taiwan. Electronic address: blyen@nhri.org.tw.
authors: B Linju
authors: BL
authors: Yen
mesh_terms: D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D055785:Gene Knockdown Techniques; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C486701:IL25 protein, human; D020381:Interleukin-17; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human