Transgenic mice expressing β1 integrins in the suprabasal epidermal layers have sporadic skin hyperproliferation and inflammation correlated with activation of extracellular signal-regulated kinase (Erk) mitogen-activated protein kinase and increased interleukin (IL)-1α production. We investigated the link between aberrant integrin expression, Erk activation, and expression of IL-1α. Transgenic keratinocytes had higher basal Erk activity and IL-1α levels than nontransgenic controls and were more sensitive to stimulation of Erk activity and IL-1α production by IL-1α, 12-O-tetradecanoylphorbol-13-acetate (TPA), epidermal growth factor (EGF), and serum. Inhibition of Erk in transgenic keratinocytes reduced basal IL-1α levels and the stimulation of IL-1α production by serum or phorbol ester, demonstrating that Erk could regulate IL-1α expression. TPA or IL-1α treatment resulted in rapid down-regulation of the EGF receptor in transgenic cells, indicative of transactivation. Inhibition of transactivation blocked basal and TPA or IL-1α induced Erk activation, but not IκBα degradation, and abolished increased IL-1α production in transgenic cells. In transgene-negative cells, constitutive activation of IL-1-dependent signaling by wild type or kinase-dead IRAK1 stimulated IL-1α production independent of Erk. We conclude that suprabasal integrin expression leads to Erk activation and increased IL-1α expression by potentiating activation of the EGF receptor. These results provide a mechanism by which aberrant integrin expression triggers epidermal hyperproliferation and inflammation.