title: EGFR regulates the expression of keratinocyte-derived granulocyte/macrophage colony-stimulating factor in vitro and in vivo.
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-alpha 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-alpha-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.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. masciaf@mail.nih.gov
authors.forename: Francesca
authors.initials: F
authors.lastname: Mascia
authors.forename: Christophe
authors.initials: C
authors.lastname: Cataisson
authors.forename: Tang-Cheng
authors.initials: TC
authors.lastname: Lee
authors.forename: David
authors.initials: D
authors.lastname: Threadgill
authors.forename: Valentina
authors.initials: V
authors.lastname: Mariani
authors.forename: Paolo
authors.initials: P
authors.lastname: Amerio
authors.forename: Chinmayi
authors.initials: C
authors.lastname: Chandrasekhara
authors.forename: Gema
authors.initials: G
authors.lastname: Souto Adeva
authors.forename: Giampiero
authors.initials: G
authors.lastname: Girolomoni
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
authors.forename: Saveria
authors.initials: S
authors.lastname: Pastore
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects; D002478:Cells, Cultured; D000068818:Cetuximab; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D003875:Drug Eruptions / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008875:Middle Aged; D010766:Phosphorylation / Q000502:physiology; D011565:Psoriasis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D014158:Transcription, Genetic / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016211:Transforming Growth Factor alpha; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D000068818:Cetuximab