1. ¹Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA
2. ²Department of Genetics and the Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
3. ³Laboratory of Tissue Engineering and Cutaneous Physiopathology, Istituto Dermopatico dell'Immacolata, IRCCS, Rome, Italy
4. ⁴Clinica Dermatologica University of Chieti-Pescara, Chieti, Italy
5. ⁵Department of Biomedical and Surgical Sciences, Section of Dermatology, University of Verona, Verona, Italy

Correspondence: Dr Francesca Mascia, Laboratory of Cancer Biology and Genetics, National Cancer Institute, CCR NIH, 37 Convent Drive, Bldg 37 Rm 4066, Bethesda, Maryland 20892, USA. E-mail: masciaf@mail.nih.gov

⁶Co-senior authors.

Received 26 March 2009; Revised 28 August 2009; Accepted 4 September 2009; Published online 5 November 2009.

Abstract

Recent advances in the knowledge of the EGFR pathway have revealed its contribution to distinct immune/inflammatory functions of the epidermis. The purpose of our study was to evaluate the role of EGFR in the regulation of keratinocyte GM-CSF expression. In cultured human keratinocytes, proinflammatory cytokines synergized with TGF- to induce GM-CSF expression. Accordingly, high epidermal levels of EGFR activation are associated with enhanced expression of GM-CSF in lesional skin of patients with psoriasis or allergic contact dermatitis. In cultured keratinocytes, pharmacological inhibition of EGFR activity reduced GM-CSF promoter transactivation, whereas genetic inhibition of AP-1 reduced expression of GM-CSF. Furthermore, EGFR activation enhanced TNF--induced c-Jun phosphorylation and DNA binding, whereas c-Jun silencing reduced GM-CSF expression. Using two different mouse models, we showed that the lack of a functional EGFR pathway was associated with reduced cytokine-induced phosphorylation of ERK1/2, JNK1/2, c-Jun and reduced keratinocyte-derived GM-CSF expression both in vitro and in vivo. Finally, the analysis of GM-CSF expression in the skin of cancer patients treated with anti EGFR drugs showed an association between ERK activity, c-Jun phosphorylation, and epidermal GM-CSF expression. These data demonstrate that the EGFR pathway is critical for the upregulation of keratinocyte GM-CSF expression under conditions of cytokine stimulation.