Modulation of sulfur mustard induced cell death in human epidermal keratinocytes using IL‐10 and TNF‐α

Abstract

We compared the effects of overexpressing a tightly regulated anti-inflammatory cytokine, interleukin 10 (IL-10), and the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) on sulfur mustard induced cytotoxicity in human epidermal keratinocytes. Both cytokines were overexpressed when compared with the cells transfected with the empty vector as determined by quantitative ELISA. Cells overexpressing interleukin 10 suppressed the pro-inflammatory cytokines interleukin 8 and interleukin 6 following exposure to 50-300 microM sulfur mustard. These cells exhibited delayed onset of sulfur mustard induced cell death. On the other hand, cells overexpressing tumor necrosis factor alpha induced a sustained elevation in both interleukin 6 and 8 expression following exposure to 50-300 microM sulfur mustard. These cells were sensitized to the effects of sulfur mustard that resulted in an increased sulfur mustard induced cell death. Normal human epidermal keratinocytes treated with sulfur mustard exhibited elevated levels of tumor necrosis factor alpha expression and increased activity of nuclear factor kappa B. Gene array data indicated that cells overexpressing interleukin 10 induced several genes that are involved in growth promotion and cell-fate determination. We, therefore, identify IL-10 and TNF-alpha signal transduction pathways and their components as possible candidates for early therapeutic intervention against sulfur mustard induced cell injury.

Time course of skin features and inflammatory biomarkers after liquid sulfur mustard exposure in SKH-1 hairless mice

“…Following SM exposure, previous studies have shown that normal human keratinocytes increase levels of IL1b, IL6, IL8 and TNFa in a dose dependent manner (Arroyo et al, 2000(Arroyo et al, , 2004 which is associated with epidermal cell death (Qabar et al, 2005;Ruff and Dillman, 2010). Our results showing a dose dependent increase of both mRNA for these inflammatory mediators and number of pyknotic nuclei in skin of hairless mice are concordant with these in vitro studies.…”

Sulfur mustard induced cytokine production and cell death: Investigating the potential roles of the p38, p53, and NF‐κB signaling pathways with RNA interference

“…Furthermore, a primary role for p38 in SM-induced cytokine production has now been demonstrated using two different approaches; RNAi and SB203580. These findings have important implications for future research given that NF-κB has long been implicated as playing a primary role in SM-induced inflammatory cytokine production [9,[12][13][14]. Similarly, p53 is widely believed to play a prodeath role in SMexposed cells [10,23,24,26,27].…”

“…Both p38 and NF-κB are activated in SM-exposed cells [7,[9][10][11], but it is NF-κB that has long been implicated as playing a primary role in SM-induced inflammatory cytokine production [9,[12][13][14]. These implications have been based on the observations that (1) SM-or SM analog-induced modulation of NF-κB activity in gel shift assays correlates with inflammatory or protection events, and (2) NF-κB exhibits proinflammatory activity in other systems [15,16].…”

Involvement of caspases and transmembrane metalloproteases in sulphur mustard-induced microvesication in adult human skin in organ culture: Directions for therapy

“…Another interesting aspect of the involvement of TACE/ADAM17 in HD-induced pathogenesis may be its role in the release of the inflammatory cytokine TNF␣. Indeed, an increase in the production of inflammatory cytokines including TNF␣ by cells in response to exposure to HD has been reported (Arroyo et al, 2000(Arroyo et al, , 2004Wormser et al, 2005;Qabar et al, 2005). Thus, inhibition of TACE/ADAM17 might temper the inflammatory reaction that accompanies HD-induced tissue damage.…”