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 angiogenesis. A growing body of evidence supports a key pathogenetic role for activated keratinocytes in the angiogenic response that accompanies psoriasis. We investigated the role of psoriatic epidermis in the aberrant expression of angiogenesis by examining the ability of pure populations of multipassaged keratinocytes obtained from the skin of normal 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 angiogenic responses in over 90% of corneas tested and potently stimulated directional migration of capillary endothelial cells in vitro. In contrast, conditioned medium from normal keratinocyte cultures was weakly positive in less than 10% of corneas assayed and failed to stimulate endothelial cell chemotaxis. Furthermore, keratinocytes from psoriatic skin 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 patients was suppressed by adding either highly purified thrombospondin-1 (125 ng) or following the addition of either normal keratinocyte-conditioned media or neutralizing interleukin-8 antibody. We conclude that psoriatic keratinocytes are phenotypically different from normal keratinocytes with respect to their angiogenic capacity and that this aberrant phenotype is attributable to a defect in the overproduction of interleukin-8 and a deficiency in the production of the angiogenesis inhibitor thrombospondin-1.
Nickoloff
B J
BJ
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Mitra
R S
RS
Varani
J
J
Dixit
V M
VM
Polverini
P J
PJ
D000328:Adult; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011565:Psoriasis / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D012867:Skin / Q000098:blood supply*; D019699:Thrombospondins
D043925:Angiogenesis Inducing Agents; D017077:Culture Media, Conditioned; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D019699:Thrombospondins