title: ERK1/2 regulates epidermal chemokine expression and skin inflammation.
abstract: Resident cell populations of the skin contribute to the inflammatory response by producing an array of chemokines, which attract leukocytes from the circulation. TNF-alpha is a major inducer of proinflammatory mediators in keratinocytes. We have recently observed that epidermal growth factor receptor (EGFR) signaling affects TNF-alpha-driven chemokine expression in epidermal keratinocytes, and its functional impairment increases the levels of crucial chemoattractants such as CCL2/MCP-1, CCL5/RANTES, and CXCL10/IFN-gamma-inducible protein-10. In this study, we report evidence that EGFR-dependent ERK1/2 activity is implicated in this mechanism. Abrogation of ERK1/2 activity with specific inhibitors increased chemokine expression in keratinocytes by enhancing mRNA stabilization. In mouse models, inflammatory response to irritants and T cell-mediated contact hypersensitivity were both aggravated when elicited in a skin area previously treated with an EGFR or a MAPK kinase 1/2 inhibitor. In contrast, impairment of p38alpha beta MAPK phosphorylation markedly attenuated these responses. Our data indicate that EGFR-dependent ERK1/2 activity in keratinocytes takes part to a homeostatic mechanism regulating inflammatory responses, and emphasize the distinct role of MAPKs as potential targets for manipulating inflammation in the skin.
authors.affiliation: Laboratory of Immunology, Istituto Dermopatico dell'Immacolata, Instituto di Ricovero e Cura a Carattere Scientifico, Roma, Italy. pastore@idi.it
authors.forename: Saveria
authors.initials: S
authors.lastname: Pastore
authors.forename: Francesca
authors.initials: F
authors.lastname: Mascia
authors.forename: Feliciana
authors.initials: F
authors.lastname: Mariotti
authors.forename: Cristina
authors.initials: C
authors.lastname: Dattilo
authors.forename: Valentina
authors.initials: V
authors.lastname: Mariani
authors.forename: Giampiero
authors.initials: G
authors.lastname: Girolomoni
mesh_terms: D000818:Animals; D018925:Chemokines / Q000235:genetics*; D003877:Dermatitis, Contact / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D018925:Chemokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3