The epidermal growth factor receptor (EGFR) is activated in cutaneous keratinocytes upon ultraviolet (UV) exposure and has been implicated in ultraviolet-(UV-)induced inflammation and skin tumorigenesis. Egfr mutant mice and EGFR inhibitors were used to investigate the hypothesis that EGFR activation augments inflammation following UV irradiation. Topical treatment of mouse skin with the EGFR inhibitor AG1478 before UV exposure suppressed UV-induced erythema, edema, mast cell infiltration, and neutrophil infiltration. Genetic ablation of Egfr and EGFR inhibition by AG1478 also suppressed the increase in the proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin-1α, KC (murine IL-8), and cyclooxygenase-2 (COX-2) after UV exposure of cultured keratinocytes. Finally, genetic ablation of inhibition of EGFR in cultured keratinocytes decreased p38 activation after UV, while inhibition of p38 kinase reduced COX-2 expression after UV. These data demonstrate that EGFR regulates multiple aspects of UV-induced inflammation and suggest activation of p38 kinase leading to increased COX-2 and cytokine expression as one mechanism through which it acts. 1. Introduction Epidermal growth factor receptor (EGFR) signaling is involved in important aspects of cutaneous biology, including the regulation of epidermal proliferation, apoptosis, cell adhesion, and migration. For example, EGFR signaling appears to be important for such adaptive biologic processes as wound healing [1]. On the other hand, excessive EGFR signaling may participate in processes that are ultimately destructive to skin, such as in the skin’s carcinogenic response to ultraviolet (UV) exposure [2–4]. Solar UV radiation is a major environmental hazard that generates reactive oxygen species, induces DNA damage, and leads ultimately to skin inflammation, photoaging, and cancer development [5]. Erythema and edema are the grossly visible signs of UV-induced inflammation in mammalian skin [6]. These changes are associated histologically with dermal infiltration of neutrophils, followed later by macrophages and mast cells [7]. These cellular events are accompanied or preceded by the release of a wide variety of proinflammatory mediators, including certain enzymes and cytokines. For example, following skin exposure to UV light, levels of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) are increased [8], which in turn leads to production of prostaglandin E2 (PGE2), a potent mediator of UV-induced skin erythema [9]. In addition to the activation of various enzymes in all nucleated cells in the
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