Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses

Wei Bei Wang, Men Luh Yen, Ko Jiunn Liu, Pei Ju Hsu, Ming Hong Lin, Pei Min Chen, Putty Reddy Sudhir, Chein Hung Chen, Chung Hsuan Chen, Huei Kang Sytwu, B. Linju Yen

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Summary 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.In this article, Yen and colleagues demonstrate that multipotent human mesenchymal stromal cells (hMSCs) suppress interleukin (IL)-17A-secreting T cell (Th17) responses through expression of IL-25, a paracrine factor, and programmed death ligand-1 (PD-L1), a cell surface ligand. The requirement of both factors is explained by IL-25 modulation of PD-L1 expression via JNK and STAT3 to orchestrate an overall effect of suppressing Th17 responses.

Original languageEnglish (US)
Pages (from-to)392-404
Number of pages13
JournalStem Cell Reports
Volume5
Issue number3
DOIs
StatePublished - Sep 8 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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