Antagonism of epidermal growth factor receptor tyrosine kinase ameliorates the psoriatic phenotype in organ-cultured skin.
Psoriatic plaque skin incubated for eight days in organ culture in the presence of a potent epidermal growth factor (EGF) receptor tyrosine kinase (RTK) antagonist reverted to a more normal histological appearance, while untreated psoriatic plaque skin retained histological features associated with the psoriatic phenotype. In concomitant studies it was shown that the EGF-RTK antagonist had no significant effect on histological features of non-psoriatic skin and no effect on dermal function, i.e. elaboration of both type I procollagen and matrix metalloproteinase-1 (MMP-1; interstitial collagenase). When human epidermal keratinocytes were treated with the EGF-RTK antagonist in monolayer culture, growth inhibition was seen (ED(50) = approximately 0.06 microM). When dermal fibroblasts were exposed to the EGF-RTK antagonist in monolayer culture, proliferation, MMP-1 and type I procollagen production were essentially unaffected at concentrations which interfered with keratinocyte growth (up to 1 microM). The capacity of the EGF-RTK antagonist to modulate the histological features of psoriatic skin in organ culture under conditions in which normal skin architecture and dermal function are largely unaffected suggests a potential for anti-psoriatic therapy.
Varani
J
J
Department of Pathology, The University of Michigan Medical School, Ann Arbor, 48109, USA. varani@umich.edu
Lateef
H
H
Fay
K
K
Elder
J T
JT
D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009924:Organ Culture Techniques; D010641:Phenotype; D011347:Procollagen / Q000096:biosynthesis; D011565:Psoriasis / Q000188:drug therapy* / Q000473:pathology; D012867:Skin / Q000737:chemistry / Q000473:pathology*
D004791:Enzyme Inhibitors; D011347:Procollagen; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1