PKR is an essential regulator of HMGB1 release (116.38)

Abstract

Abstract High-mobility group box 1 (HMGB1), a leader-less proinflammatory cytokine, is a necessary and sufficient mediator of inflammation during sterile and infectious injury. However, the mechanism of HMGB1 release by activated immune cells is largely unknown. Here we demonstrate that macrophages stimulated with Type 1 interferon release HMGB1 in a dose- and time- dependent manner. Consistently, inhibition of JAK-STAT pathway attenuated Type 1 interferon-induced HMGB1 release. Analysis of downstream effectors demonstrated that Interferon-inducible double-stranded RNA activated protein kinase R (PKR) is essential for Type 1 interferon mediated HMGB1 release. Inhibition of PKR activity by using specific inhibitor reduced Type 1 interferon-induced HMGB1 release in a dose dependent manner. Inhibition of PKR activity also blocked LPS- and Poly I:C- induced HMGB1 release from macrophages. Using immunohistochemical analysis, we have identified two important steps in HMGB1 release by activated macrophages. The first step is mediated by activation of JAK-STAT pathway by Type 1 interferon that culminates into translocation of HMGB1 from nucleus to cytoplasm. This is followed by PKR activation that in turn regulates HMGB1 release by macrophages. Our studies indicate that PKR is an essential regulator of HMGB1 release induced by multiple stimuli, such as Type 1 interferon, LPS and Poly I:C.