ABERRANT PRODUCTION OF INTERLEUKIN-8 AND THROMBOSPONDIN-1 BY PSORIATIC KERATINOCYTES MEDIATES ANGIOGENESIS

Psoriasis is a common inherited skin disease that is characterized by hyperproliferation of epidermal keratinocytes and excessive dermal ang iogenesis. A growing body of evidence supports a key pathogenetic role for activated keratinocytes in the angiogenic response that accompani es psoriasis. We investigated the role of psoriatic epidermis in the a berrant expression of angiogenesis by examining the ability of pure po pulations of multipassaged keratinocytes obtained from the skin of nor mal individuals and psoriatic patients to induce angiogenesis in vivo in the rat corneal bioassay and endothelial cell chemotaxis in vitro. Media conditioned by keratinocytes from psoriatic patients, including both symptomless skin and psoriatic plaques, induced vigorous angiogen ic responses in over 90% of corneas tested and potently stimulated dir ectional migration of capillary endothelial cells in vitro. In contras t, conditioned medium from normal keratinocyte cultures was weakly pos itive in less than 10% of corneas assayed and failed to stimulate endo thelial cell chemotaxis. Furthermore, keratinocytes from psoriatic ski n exhibited a 10- to 20-fold increase in interleukin-8 production and a seven-fold reduction in thrombospondin-1 production. The angiogenic activity present in keratinocyte-conditioned media from psoriatic pati ents was suppressed by adding either highly purified thrombospondin-1 (125 ng) or following the addition of either normal keratinocyte-condi tioned media or neutralizing interleukin-8 antibody. We conclude that psoriatic keratinocytes are phenotypically different from normal kerat inocytes with respect to their angiogenic capacity and that this aberr ant phenotype is attributable to a defect in the overproduction of int erleukin-8 and a deficiency in the production of the angiogenesis inhi bitor thrombospondin-1.