Effect of heme oxygenase-1 on the expression of interferon-stimulated genes

Abstract

Heme oxygenase-1 (HO1, Hmox1) degrades excess heme and is considered an anti-oxidative and anti-inflammatory enzyme. Our previous studies in Hmox1 knockout mice revealed induction of interferon-stimulated genes (ISGs) in all cell types analyzed, despite unchanged interferon production. Here, we sought to identify the pathway underlying HO1-dependent ISG regulation and determine how ISG expression changes in cultured cells in response to stressors typical of Hmox1-deficient mice. Using murine wild-type and Hmox1-deficient (KO-Hmox1) fibroblasts, we showed that in cells cultured under control conditions, the expression of most of the tested ISGs was independent of cellular HO1 status. We then analyzed the effect of extrinsic stressors: hemolytic, oxidative, genotoxic, and replication stress, proinflammatory TNF, and endogenous heme overload. TNF (upregulated in Hmox1 knockout mice) was the sole and universal ISG inducer in both wild-type and KO-Hmox1 fibroblasts. Unexpectedly, the response of KO-Hmox1 cells to exogenous TNF was weakened, probably due to impaired NF-{kappa}B activity and reduced p65 nuclear retention. A similar decrease we observed for STAT1. Additionally, the presence of TREX1 exonuclease in the nucleus indicated impaired nuclear envelope integrity. Noteworthy, HO1 colocalizes with PARP1, a protein regulating cytoplasmic-nuclear transport. Olaparib-mediated PARP1 inhibition abolished TNA-induced nuclear accumulation of p65 and STAT1 in wild-type cells, but not in KO-Hmox1 counterparts. In summary, the inflammation typical of Hmox1-deficient mice appears to be a major inducer of ISGs in vivo. Despite this, the inflammatory response to exogenous TNF is attenuated in KO-Hmox1 cells, likely due to decreased nuclear retention of NF-{kappa}B and STAT1.