Interleukin-6 induces expression of Ifi202, an interferon-inducible candidate gene for lupus susceptibility.
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease. In human SLE patients, as well as in mouse models of SLE, the development of disease is associated with increased levels of pro-inflammatory cytokines, such as interleukin-6 (IL-6). However, IL-6 target genes contributing to the development of disease remain to be identified. Our previous studies of one mouse model of SLE identified an interferon-inducible gene, Ifi202, as a major contributor to the disease. We now report that IL-6 induces expression of the Ifi202 gene. We found that IL-6 treatment of mouse splenocytes increased levels of Ifi202 mRNA and p202 protein. Furthermore, IL-6 treatment of NIH 3T3 cells or expression of a constitutively active form of STAT3, a known mediator of IL-6 signaling, stimulated the activity of a 202-luc-reporter through a potential STAT3 DNA-binding site (the 202-SBS) present in the 5'-regulatory region of the Ifi202 gene. Moreover, treatment of cells with IL-6 stimulated binding of the transcription factor STAT3 to an oligonucleotide containing the 202-SBS in gel-mobility shift assays and to the 5'-regulatory region of the Ifi202 gene in chromatin immunoprecipitation assays. Importantly, site-directed mutagenesis of 202-SBS or expression of a dominant negative form of STAT3 significantly reduced constitutive as well as IL-6-stimulated activity of the 202-luc-reporter. Together, our observations support the idea that IL-6 stimulates transcription of the Ifi202 gene through STAT3 activation and predict that increased levels of IL-6 in lupus contribute to up-regulation of p202.
Pramanik
Rocky
R
Department of Radiation Oncology, Stritch School of Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Jørgensen
Trine N
TN
Xin
Hong
H
Kotzin
Brian L
BL
Choubey
Divaker
D
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D007372:Interferons; D015850:Interleukin-6 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D002352:Carrier Proteins; C092537:Ifi202b protein, mouse; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D007372:Interferons