Down-regulation of MHC-II in mesenchymal stem cells at high IFN-γ can be partly explained by cytoplasmic retention of CIITA

Katherine C. Tang, Katarzyna A. Trzaska, Sergey V. Smirnov, Sergei V. Kotenko, Stephan K. Schwander, Jerrold J. Ellner, Pranela Rameshwar

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Abstract

Mesenchymal stem cells (MSCs) are located in postnatal bone marrow, show plasticity, are linked to various bone marrow disorders, exhibit phagocytosis, exert Ag-presenting properties (APC), and are immune suppressive. Unlike professional APCs, MSCs respond bimodally to IFN-γ in MHC-II expression, with expression at 10 U/ml and baseline, and down-regulation at 100 U/ml. The effects at high IFN-γ could not be explained by down-regulation of its receptor, IFN-γRI. In this study, we report on the mechanisms by which IFN-γ regulates MHC-II expression in MSCs. Gel shift assay and Western blot analyses showed dose-dependent increases in activated STAT-1, indicating responsiveness by IFN-γRI. Western blots showed decreased intracellular MHC-II, which could not be explained by decreased transcription of the master regulator CIITA, based on RT-PCR and in situ immunofluorescence. Reporter gene assays with PIII and PIV CIITA promoters indicate constitutive expression of PIII in MSCs and a switch to PIV by IFN-γ, indicating the presence of factors for effect promoter responses. We explained decreased MHC-II at the level of transcription because CIITA protein was observed in the cytosol and not in nuclei at high IFN-γ level. The proline/serine/threonine region of CIITA showed significant decrease in phosphorylation at high IFN-γ levels. An understanding of the bimodal effects could provide insights on bone marrow homeostasis, which could be extrapolated to MSC dysfunction in hematological disorders.

Original languageEnglish (US)
Pages (from-to)1826-1833
Number of pages8
JournalJournal of Immunology
Volume180
Issue number3
Publication statusPublished - Feb 1 2008
Externally publishedYes

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ASJC Scopus subject areas

  • Immunology

Cite this

Tang, K. C., Trzaska, K. A., Smirnov, S. V., Kotenko, S. V., Schwander, S. K., Ellner, J. J., & Rameshwar, P. (2008). Down-regulation of MHC-II in mesenchymal stem cells at high IFN-γ can be partly explained by cytoplasmic retention of CIITA. Journal of Immunology, 180(3), 1826-1833.