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Down-Regulation of MHC II in Mesenchymal Stem Cells at High IFN- Can Be Partly Explained by Cytoplasmic Retention of CIITA¹

Katherine C. Tang^2,*,, Katarzyna A. Trzaska^2,*,, Sergey V. Smirnov, Sergei V. Kotenko, Stephan K. Schwander, Jerrold J. Ellner and Pranela Rameshwar^3,

^* Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103; Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103; and University Hospital Cancer Center-Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103

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- in MHC-II expression, with expression at 10 U/ml and baseline, and down-regulation at 100 U/ml. The effects at high IFN- could not be explained by down-regulation of its receptor, IFN-RI. In this study, we report on the mechanisms by which IFN- 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-RI. 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-, 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- level. The proline/serine/threonine region of CIITA showed significant decrease in phosphorylation at high IFN- levels. An understanding of the bimodal effects could provide insights on bone marrow homeostasis, which could be extrapolated to MSC dysfunction in hematological disorders.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work, which was done at the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, was supported by FM Kirby Foundation. This work was in partial fulfillment for a PhD thesis (K.A.T.).

² K.C.T. and K.A.T. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Pranela Rameshwar, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, MSB, Room E-579, 185 South Orange Avenue, Newark, NJ 07103. E-mail address: rameshwa{at}umdnj.edu

⁴ Abbreviations used in this paper: HSC, hemopoietic stem cell; GAS, IFN--activated sequence; LRR, leucine-rich repeat; MSC, mesenchymal stem cell; NLS, nuclear localization signal; p-STAT-1, phosphorylated STAT-1; P/S/T, proline/ serine/threonine.