Dysregulation of the IFN-γ-STAT1 signaling pathway in a cell line model of large granular lymphocyte leukemia

PloS One
Paige M KullingThomas P Loughran

Abstract

T cell large granular lymphocyte leukemia (T-LGLL) is a rare incurable disease that is characterized by defective apoptosis of cytotoxic CD8+ T cells. Chronic activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a hallmark of T-LGLL. One manifestation is the constitutive phosphorylation of tyrosine 701 of STAT1 (p-STAT1). T-LGLL patients also exhibit elevated serum levels of the STAT1 activator, interferon-γ (IFN-γ), thus contributing to an inflammatory environment. In normal cells, IFN-γ production is tightly controlled through induction of IFN-γ negative regulators. However, in T-LGLL, IFN-γ signaling lacks this negative feedback mechanism as evidenced by excessive IFN-γ production and decreased levels of suppressors of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ. Here we characterize the IFN-γ-STAT1 pathway in TL-1 cells, a cell line model of T-LGLL. TL-1 cells exhibited lower IFN-γ receptor protein and mRNA expression compared to an IFN-γ responsive cell line. Furthermore, IFN-γ treatment did not induce JAK2 or STAT1 activation or transcription of IFN-γ-inducible gene targets. However, IFN-β induced p-STAT1 and subsequent STAT1 gene transcription, demonstratin...Continue Reading

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Citations

Jun 8, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Zahra Tavakoli Dargani, Dinender K Singla
Jul 24, 2020·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Ailin ElyasiAllison B Reiss
Nov 19, 2019·International Journal of Biological Macromolecules·Jing ZhangGang Zhou
Jun 11, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Mohamed ElbadawiThomas Efferth
Aug 27, 2021·ERJ Open Research·Maysa AlhawmdehMojgan Najafzadeh

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Methods Mentioned

BETA
flow cytometry
flow
protein assay
Assay
Transfection
PCR
FCS

Software Mentioned

Image Lab

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