Local cortisol activation is involved in EGF-induced immunosuppression

Area of Science:

• Dermatology
• Immunology
• Endocrinology

Background:

• Epidermal Growth Factor Receptor (EGFR) signaling impacts keratinocyte proliferation, differentiation, and wound healing.
• EGFR signaling also exhibits immunosuppressive effects, but the underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of local cortisol activation in EGFR signaling-induced immunosuppression in keratinocytes.
• To elucidate the mechanism by which EGFR signaling influences immune responses in skin.

Main Methods:

• Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and ELISA assays were used to measure gene and protein expression.
• Keratinocytes were treated with EGF, TNF-α, 11β-HSD1 inhibitors, and cetuximab.
• 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) expression and activity were assessed.

Main Results:

• EGF treatment dose-dependently increased 11β-HSD1 expression and cortisol levels in keratinocytes.
• EGFR signaling and 11β-HSD1 overexpression reduced TNF-α-induced IL-6 expression.
• Inhibition of 11β-HSD1 reversed the immunosuppressive effects of EGF on IL-6 production.
• Cetuximab, an EGFR inhibitor, decreased 11β-HSD1 transcript levels, particularly in TNF-α-treated cells.

Conclusions:

• Increased local cortisol activation by 11β-HSD1 is a key mechanism in EGFR signaling-induced immunosuppression in keratinocytes.
• This pathway may contribute to adverse skin reactions observed in patients treated with EGFR inhibitors, linking inflammation and cell proliferation.