Lee, Hyejin
(Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine)
,
Cheong, Kyung Ah
(Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine)
,
Kim, Ji-Young
(Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine)
,
Kim, Nan-Hyung
(Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine)
,
Noh, Minsoo
(Department of Pharmacy, College of Pharmacy, Seoul National University)
,
Lee, Ai-Young
(Department of Dermatology, Dongguk University Seoul, Graduate School of Medicine)
Extracellular interleukin 1 alpha (IL-$1{\alpha}$) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-$1{\alpha}$ is not released in apoptotic...
Extracellular interleukin 1 alpha (IL-$1{\alpha}$) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-$1{\alpha}$ is not released in apoptotic cells. On the other hand, active secretion has been identified in interleukin-1 receptor antagonist (IL-1ra), which was discovered to be a common, upregulated, differentially-expressed gene in a microarray analysis performed with keratinocytes treated using cytotoxic doses of chemicals. This study examined whether and how IL-1ra, particularly extracellularly released IL-1ra, was involved in chemically-induced keratinocyte cytotoxicity and skin irritation. Primary cultured normal adult skin keratinocytes were treated with cytotoxic doses of chemicals (hydroquinone, retinoic acid, sodium lauryl sulfate, or urshiol) with or without recombinant IL-1ra treatment. Mouse skin was administered irritant concentrations of hydroquinone or retinoic acid. IL-1ra (mRNA and/or intracellular/extracellularly released protein) levels increased in the chemically treated cultured keratinocytes with IL-$1{\alpha}$ and IL-$1{\beta}$ mRNAs and in the chemically exposed epidermis of the mouse skin. Recombinant IL-1ra treatment significantly reduced the chemically-induced apoptotic death and intracellular/extracellularly released IL-$1{\alpha}$ and IL-$1{\beta}$ in keratinocytes. Collectively, extracellular IL-1ra released from keratinocytes could be a compensatory mechanism to reduce the chemically-induced keratinocyte apoptosis by antagonism to IL-$1{\alpha}$ and IL-$1{\beta}$, suggesting potential applications to predict skin irritation.
Extracellular interleukin 1 alpha (IL-$1{\alpha}$) released from keratinocytes is one of the endpoints for in vitro assessments of skin irritancy. Although cells dying via primary skin irritation undergo apoptosis as well as necrosis, IL-$1{\alpha}$ is not released in apoptotic cells. On the other hand, active secretion has been identified in interleukin-1 receptor antagonist (IL-1ra), which was discovered to be a common, upregulated, differentially-expressed gene in a microarray analysis performed with keratinocytes treated using cytotoxic doses of chemicals. This study examined whether and how IL-1ra, particularly extracellularly released IL-1ra, was involved in chemically-induced keratinocyte cytotoxicity and skin irritation. Primary cultured normal adult skin keratinocytes were treated with cytotoxic doses of chemicals (hydroquinone, retinoic acid, sodium lauryl sulfate, or urshiol) with or without recombinant IL-1ra treatment. Mouse skin was administered irritant concentrations of hydroquinone or retinoic acid. IL-1ra (mRNA and/or intracellular/extracellularly released protein) levels increased in the chemically treated cultured keratinocytes with IL-$1{\alpha}$ and IL-$1{\beta}$ mRNAs and in the chemically exposed epidermis of the mouse skin. Recombinant IL-1ra treatment significantly reduced the chemically-induced apoptotic death and intracellular/extracellularly released IL-$1{\alpha}$ and IL-$1{\beta}$ in keratinocytes. Collectively, extracellular IL-1ra released from keratinocytes could be a compensatory mechanism to reduce the chemically-induced keratinocyte apoptosis by antagonism to IL-$1{\alpha}$ and IL-$1{\beta}$, suggesting potential applications to predict skin irritation.
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가설 설정
, 2005; Stratigos and Katsambas, 2005). In this study, we examined whether IL-1ra, particularly extracellularly released IL-1ra, could be involved in keratinocyte apoptosis and skin irritation due to chemicals, including these depigmenting agents. IL-1ra mRNA and/or protein expression increased time- and/or dose-dependently in primary cultured normal human keratinocytes and mouse skin after applying different cytotoxic concentrations of depigmenting chemicals (HQ and RA), a representative irritant (SLS), or a representative sensitizer (urshiol).
제안 방법
SLS (Sigma Aldrich) was solved in distilled water (DW) to produce a stock solution. For the in vivo studies, HQ was prepared as 10% and 20% and RA as 0.1% and 0.5% in a petrolatum base. Recombinant human interleukin-1 receptor antagonist (rhIL-1ra; R&D Systems, Minneapolis, MA, USA) was diluted using phosphate buffered saline (PBS).
The biological effects of keratinocyte-derived IL-1ra, particularly on keratinocyte apoptosis or survival, have not been studied extensively. In this study, the effect of rhIL-1ra on cell survival was examined based on the opposite correlation between cell survival and IL-1ra, particularly extracellularly released IL-1ra in culture supernatants (Fig. 2B). The results of the MTT assay show that rhIL-1ra attenuated the chemicalinduced keratinocytes death in a dose-dependent manner in the range of up to 500 ng/ml without effecting any changes in unstimulated keratinocytes (Fig.
이론/모형
The cell viability was evaluated using the MTT reduction method. The cells were stained with MTT for 4 hrs.
성능/효과
Statistical analysis The statistical significance was assessed using Student’s t tests, and a p-value of less than 0.05 is considered statistically significant.
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