Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses
Journal
Stem Cell Reports
Journal Volume
5
Journal Issue
3
Pages
392-404
ISSN
2213-6711
Date Issued
2015
Author(s)
Liu K.-J
Hsu P.-J
Lin M.-H
Chen P.-M
Sudhir P.-R
Chen C.-H
Chen C.-H
Sytwu H.-K
Yen B.L.
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. © 2015 The Authors.
Type
journal article