REDD‐1 aggravates endotoxin‐induced inflammation VIA atypical NF‐κB activation

Abstract

Regulated in development and DNA damage responses 1 (REDD-1), an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1 macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-κB activation was independent of 2 classic IKK-dependent NF-κB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IκBα, to elicit atypical NF-κB activation during the delayed and persistent phases of inflammation after stimulation. Moreover, REDD-1 knockdown mitigated vascular inflammation and permeability in endotoxemic mice, resulting in decreases in immune cell infiltration, systemic inflammation, caspase-3 activation, apoptosis, and consequent mortality. We further confirmed the inflammatory and cytotoxic effects of REDD-1 in endotoxemic REDD-1 mice. Our data support the likelihood that REDD-1 exacerbates endotoxemic inflammation via atypical NF-κB activation by sequestering IκBα.-Lee, D.-K., Kim, J.-H., Kim, J., Choi, S., Park, M., Park, W., Kim, S., Lee, K.-S., Kim, T., Jung, J., Choi, Y. K., Ha, K.-S., Won, M.-H., Billiar, T. R., Kwon, Y.-G., Kim, Y.-M. REDD-1 aggravates endotoxin-induced inflammation via atypical NF-κB activation.

Redd1 knockdown prevents doxorubicin-induced cardiac senescence

“…Redd1 expression is stimulated by cellular stress and influences a wide spectrum of cellular processes mainly through inhibition of mTOR signaling [ 22 – 25 ]. It was reported that Redd1 expression in the hippocampus increases markedly during normal aging, suggesting that Redd1 is an aging-associated factor [ 32 ].…”

“…Regulated in development and DNA damage response-1 (Redd1), also known as DNA Damage-Inducible Transcript 4 (DDIT4), is a stress-response gene that is transcriptionally induced in various types of cells by stressful stimuli such as DNA damage, hypoxia, and energy deficits [ 20 , 21 ]. Redd1 is a potent inhibitor of mammalian Target of Rapamycin (mTOR) Complex-1 (mTORC1), and its expression influences a wide spectrum of cellular processes and biological functions, such as cell cycle, autophagy, energy homeostasis, and inflammation [ 22 – 25 ]. A regulatory role for Redd1 was reported in phenylephrine-induced cardiac hypertrophy [ 26 ] and myocardial ischemia/reperfusion injury [ 27 , 28 ].…”

DDIT4 Novel Mutations in Pancreatic Cancer

“…Meanwhile, the abnormal function of immune cells was involved in tumor resistance of pancreatic cancer. DDIT4 enhanced vascular inflammation and permeability in endotoxemia mice, leading to immune cell infiltration, systemic inflammation, caspase-3 activation, and apoptosis [ 27 ]. DDIT4 was related to the low level of reactive oxygen species of mitochondria in macrophages induced by IL-10 or hypoxia [ 28 ], and it inhibited the immune function of macrophages.…”

Strongylocentrotusnudos Egg Polysaccharide induces autophagy and apoptosis in leukaemia cells by regulating mitochondrial function

“…Mitochondrial‐mediated regulation of autophagy has both a direct and indirect relationship with the onset of tumours and represents a key regulator of quality control in tumour cells. The outcome of activation of the autophagy pathway may differ depending on the stage of tumour development 45 . In this experiment, the relationship between NF‐κB and the activation of autophagy was examined by investigating the activation of LC3‐II protein.…”