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ABSTRACT
The major effects of the epidermal growth factor receptor (EGFR) signalling pathway on keratinocytes are cell proliferation, cell differentiation, and wound healing. In addition to these effects, an immunosuppressive effect of EGFR signalling has been reported. However, the precise mechanism of immunosuppression by EGFR signalling is not well understood.
In this study, we clarified the involvement of increased local cortisol activation in EGFR signalling-induced immunosuppression in keratinocytes.
EGF treatment up-regulated the expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and supernatant cortisol levels in a dose-dependent manner in keratinocytes. 11β-HSD1 is an enzyme that catalyses the conversion of cellular hormonally inactive cortisone into active cortisol. qRT-PCR and ELISA assays indicated that EGF significantly decreased tumour necrosis factor α (TNF- α)-induced interleukin-6 (IL-6) expression in keratinocytes. Similarly, 11β-HSD1 overexpression significantly decreased TNF-α-induced IL-6 expression. We evaluated the role of 11β-HSD1 in immunosuppression through EGFR signalling. Blockade of 11β-HSD1 via 11β-HSD1 inhibitor reversed both the expression and production of TNF-α-induced IL-6, which was decreased by EGF in keratinocytes. Therefore, increased local cortisol activation by 11β-HSD1 is involved in EGFR signalling-induced immunosuppression in keratinocytes.
Finally, we evaluated whether EGFR inhibition by cetuximab affects the expression of 11β-HSD1. We found that 0.1 µg cetuximab decreased 11β-HSD1 transcript levels in keratinocytes. The changes in 11β-HSD1 were more apparent in TNF-α-treated cells.
As 11β-HSD1 expression in keratinocytes is associated with inflammation and cell proliferation, this mechanism may be associated with adverse skin reactions observed in patients treated with EGFR inhibitors.
Abbreviations
| ANOVA | = | Analysis of variance |
| EGFR | = | epidermal growth factor receptor |
| ELISA | = | Enzyme-linked immunosorbent assay |
| GAPDH | = | Glyceraldehyde-3-phosphate dehydrogenase |
| IL-6 | = | interleukin-6 |
| NHEK | = | Normal epidermal human keratinocytes |
| siRNA | = | Small interfering RNA |
| SD | = | standard deviation |
| SDS-PAGE | = | sodium dodecyl sulfide-polyacrylamide |
| TNF-α | = | tumour necrosis factor α |
| qRT-PCR | = | quantitative reverse transcriptase-polymerase chain reaction |
| 11-DHC | = | 11-dehydrocorticosterone |
| 11β-HSD1 | = | 11β-hydroxysteroid dehydrogenase 1 |
Disclosure of potential conflict of interest
No potential conflicts of interest were disclosed.
Acknowledgments
The authors thank Mr. Kenju Nishida, Ms. Eriko Nobuyoshi, and Ms. Yumiko Fujii for research assistance.