Epidermal activation of Erk MAPK is observed in human psoriatic lesions and in a mouse model of psoriasis in which beta1 integrins are expressed in the suprabasal epidermal layers. Constitutive activation of the upstream kinase MEK1 causes hyperproliferation and perturbed differentiation of human keratinocytes in culture. It is not known, however, whether Erk activation in differentiating keratinocytes is sufficient to trigger hyperproliferation of basal keratinocytes and a skin inflammatory infiltrate. To investigate this, we expressed constitutively active MEK1 in the suprabasal epidermal layers of transgenic mice. Proliferation in the epidermal basal layer was stimulated and epidermal terminal differentiation was perturbed. Some older mice also developed papillomas. There was a large increase in T lymphocytes, dendritic cells, and neutrophils in the skin. The effects of suprabasal MEK1 on basal keratinocytes and leukocytes, cells that were transgene negative, suggested that MEK1 activity might stimulate cytokine release. Transgenic keratinocytes expressed elevated IL-1alpha and crossing the mice with mice overexpressing the IL-1 receptor in the epidermal basal layer led to exacerbated hyperproliferation and inflammation. These data suggest that activation of MEK1 downstream of beta1 integrins plays an important role in epidermal hyperproliferation and skin inflammation.