| First Author | Lee DK | Year | 2018 |
| Journal | FASEB J | Volume | 32 |
| Issue | 8 | Pages | 4585-4599 |
| PubMed ID | 29547704 | Mgi Jnum | J:275602 |
| Mgi Id | MGI:6307663 | Doi | 10.1096/fj.201701436R |
| Citation | Lee DK, et al. (2018) REDD-1 aggravates endotoxin-induced inflammation via atypical NF-kappaB activation. FASEB J 32(8):4585-4599 |
| abstractText | 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-kappaB (NF-kappaB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1(+/-) macrophages. REDD-1 overexpression stimulated NF-kappaB-dependent inflammation without additional LPS stimulation. REDD-1-induced NF-kappaB activation was independent of 2 classic IKK-dependent NF-kappaB pathways and the mTOR signaling pathway; however, REDD-1, particularly its C-terminal region (178-229), interacted with and sequestered IkappaBalpha, to elicit atypical NF-kappaB 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-kappaB activation by sequestering IkappaBalpha.-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-kappaB activation. |
