EGFR regulates the expression of keratinocyte-derived granulocyte/ macrophage colony-stimulating factor in vitro and in vivo

Francesca Mascia, Christophe Cataisson, Tang Cheng Lee, David Threadgill, Valentina Mariani, Paolo Amerio, Chinmayi Chandrasekhara, Gema Souto Adeva, Giampiero Girolomoni, Stuart H. Yuspa, Saveria Pastore

Research output: Contribution to journalArticlepeer-review

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-α 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-α-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.

Original languageEnglish
Pages (from-to)682-693
Number of pages12
JournalJournal of Investigative Dermatology
Volume130
Issue number3
DOIs
Publication statusPublished - Mar 2010

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Cell Biology
  • Molecular Biology

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