Transforming growth factor-beta receptor binding and function are decreased in psoriatic dermal endothelium

T lymphocytes adhere to dermal microvascular endothelial cells (DMEC) as the first step in their emigration from the blood vasculature into diseased skin. Earlier studies have shown that the adhesiveness of cultured DMEC from normal skin for lymphocytes can be blocked by transforming growth factor-beta 1 (TGF-beta 1). In contrast, TGF-beta 1 has no effect on the adhesive properties of DMEC from psoriatic plaques, and this response is attenuated by the addition of interleukin-4 (IL-4). In the present study, we show that both TGF-beta 1 and TGF-beta 2, and to a lesser extent TGF-beta 3 isoforms block the ability of normal but not psoriatic DMEC to bind lymphocytes. Pretreatment with TGF-beta 1 selectively inhibited the tumor necrosis factor-alpha (TNF-alpha)-stimulated expression of E-selectin on normal DMEC but had no effect on psoriatic DMEC. Scatchard analysis revealed both low- and high-affinity receptors on normal DMEC, The baseline number of high-affinity TGF-beta receptors was significantly reduced on psoriatic DMEC, whereas IL-4 treatment of DMEC altered the binding affinity but not the number of receptors, The protein and mRNA transcripts of type I and type II TGF-beta receptor genes were detectable in psoriatic DMEC. A reduction in the autophosphorylation of the TGF-beta type II receptor protein, a constitutively active serine/threonine kinase, however, was detected in psoriatic DMEC. These in vitro findings suggest that reduction of TGF-beta receptor expression and function may contribute to lymphocyte infiltration into psoriatic plaques irt vivo by allowing dermal microvascular endothelium to escape from the negative regulation by TGF-beta.