Interleukin-6 Induces Expression of Ifi202, an Interferon-inducible Candidate Gene for Lupus Susceptibility

Abstract

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 upregulation of p202.