Transforming growth factor-beta receptor binding and function are decreased in psoriatic dermal endothelium.
T lymphocyte 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-beta1 (TGF-beta1). In contrast, TGF-beta1 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-beta1 and TGF-beta2, and to a lesser extent TGF-beta3 isoforms block the ability of normal but not psoriatic DMEC to bind lymphocytes. Pretreatment with TGF-beta1 selectively inhibited the tumor necrosis factor-alpha(TNF-alpha)-stimulated expression of E-selecting on normal DMEC but had no 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 the TGF-beta type II receptor protein, a constitutively active serine/threonine kinase, however, was detected in psoriatic DMEC. These in vitro finding suggest that reduction of TGF-beta receptor expression and function may contribute to lymphocyte infiltration into psoriatic plaques in vivo by allowing dermal microvascular endothelium to escape form the negative regulation by TGF-beta.
Cai
J P
JP
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33101, USA.
Falanga
V
V
Taylor
J R
JR
Chin
Y H
YH
D015152:Blotting, Northern; D002448:Cell Adhesion / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019040:E-Selectin / Q000096:biosynthesis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008833:Microcirculation; D010766:Phosphorylation; D011565:Psoriasis / Q000378:metabolism* / Q000503:physiopathology*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology*; D012867:Skin / Q000737:chemistry*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D003432:Cross-Linking Reagents; D019040:E-Selectin; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha