Stimulation of T cells up-regulates expression of Ifi202, an interferon-inducible lupus susceptibility gene, through activation of JNK/c-Jun pathway.
Studies have revealed that increased expression of interferon (IFN)-inducible Ifi202 gene (encoding p202 protein) in splenic B and T cells from B6.Nba2 congenic (congenic for Nb2 locus derived from NZB mice) female mice is associated with lupus susceptibility. However, signaling pathways that regulate Ifi202 expression in immune cells remain to be elucidated. Here we report that stimulation of T cells up-regulates the Ifi202 expression. We found that steady-state levels of Ifi202 mRNA and protein were detectable in splenic T cells from NZB mice and stimulation of T cells with anti-CD3 and anti-CD28 up-regulated expression of the Ifi202 gene. Similarly, stimulation of cells of a mouse T cell hybridoma cell line (2B4.11) also activated transcription of the Ifi202 gene. Significantly, up-regulation of Ifi202 expression in stimulated T cells was inhibited by treatment of cells with SP600125, a specific inhibitor of c-Jun N-terminal kinase (JNK). Conversely, treatment of cells with anisomycin, a potent activator of the JNK and c-Jun, up-regulated Ifi202 expression. Consistent with the activation of JNK/c-Jun pathway by T cell stimulation, forced expression of c-Jun in 2B4 T cells and in mouse embryonic fibroblasts (MEFs) also up-regulated the Ifi202 expression. Furthermore, we found that stimulation of T cells increased association of the activated c-Jun to the 5'-regulatory region of the Ifi202 gene in chromatin immunoprecipitation assays (ChIPs). Together, our observations demonstrate that stimulation of T cells up-regulates the Ifi202 expression in part through the JNK/c-Jun pathway.
Chen
Jianming
J
Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL 60153, USA.
Panchanathan
Ravichandran
R
Choubey
Divaker
D
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006825:Hybridomas; D051550:I-kappa B Kinase / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
C092537:Ifi202b protein, mouse; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases