IFN regulatory factor (IRF) 3/7-dependent and -independent gene induction by mammalian DNA that escapes degradation.

DNase II in macrophages cleaves the DNA of engulfed apoptotic cells and of nuclei expelled from erythroid precursor cells. Macrophages in DNase II-deficient mice accumulate undigested DNA and constitutively produce IFN-beta as well as TNF-alpha. The IFN-beta causes severe anemia in the DNase II(-/-) embryos, which die prenatally. On the other hand, when the DNase II gene is inactivated postnatally, mice develop polyarthritis owing to the TNF-alpha produced by macrophages. Here, we showed that the IFN-beta gene activation in DNase II(-/-) mice is dependent on IFN regulatory factor (IRF) 3 and 7. Accordingly, DNase II(-/-)IRF3(-/-)IRF7(-/-) mice do not suffer from anemia, but they still produce TNF-alpha, and age-dependently develop chronic polyarthritis. A microarray analysis of the gene expression in the fetal liver revealed a set of genes that is induced in DNase II(-/-) mice in an IRF3/IRF7-dependent manner, and another set that is induced independent of these factors. These results indicate that the mammalian chromosomal DNA that accumulates in macrophages due to inefficient degradation activates genes in both IRF3/IRF7-dependent and -independent manners.