Sulfur mustard induced cytokine production and cell death: investigating the potential roles of the p38, p53, and NF-kappaB signaling pathways with RNA interference.
Cutaneous and ocular injuries caused by sulfur mustard (SM; bis-(2-chloroethyl) sulfide) are characterized by severe inflammation and death of exposed cells. Given the known roles of p38MAPK and NF-kappaB in inflammatory cytokine production, and the known roles of NF-kappaB and p53 in cell fate, these pathways are of particular interest in the study of SM injury. In this study, we utilized inhibitory RNA (RNAi) targeted against p38 alpha, the p50 subunit of NF-kappaB, or p53 to characterize their role in SM-induced inflammation and cell death in normal human epidermal keratinocytes (NHEK). Analysis of culture supernatant from 200 microM SM-exposed cells showed that inflammatory cytokine production was inhibited by p38 alpha RNAi but not by NF-kappaB p50 RNAi. These findings further support a critical role for p38 in SM-induced inflammatory cytokine production in NHEK and suggest that NF-kappaB may not play a role in the SM-induced inflammatory response of this cell type. Inhibition of NF-kappaB by p50 RNAi did, however, partially inhibit SM-induced cell death, suggesting a role for NF-kappaB in SM-induced apoptosis or necrosis. Interestingly, inhibition of p53 by RNAi potentiated SM-induced cell death, suggesting that the role of p53 in SM injury, may be complex and not simply prodeath.
Ruff
Albert L
AL
Cell and Molecular Biology Branch, Research Division, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.
Dillman
James F
JF
D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D009151:Mustard Gas / Q000633:toxicity*; D016328:NF-kappa B / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D016207:Cytokines; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; D009151:Mustard Gas