Pervanadate mimics IFNgamma-mediated induction of ICAM-1 expression via activation of STAT proteins.
Differential expression of intercellular adhesion molecule-1 (ICAM-1) in the epidermis plays a critical role in the regulation of cutaneous inflammation, immunologic reactions, and tissue repair. Transcriptional upregulation of ICAM-1 in response to interferon-gamma (IFNgamma) occurs through a palindromic response element pIgammaRE. pIgammaRE is homologous to IFNgamma-activated sequences, which bind to tyrosine phosphorylated members of the transcription factor family known as signal transducers and activators of transcription (STAT). The importance of tyrosine phosphorylation events in the STAT pathway led us to investigate the effect of the protein tyrosine phosphatase inhibitor, pervanadate, on ICAM-1 expression. We show that treatment of A431 cells and human keratinocytes with pervanadate stimulates protein complex formation on pIgammaRE in a time- and concentration-dependent manner. As demonstrated by mobility supershift assays, the pervanadate-stimulated complex is similar to the IFNgamma-stimulated complex and contains Stat1. Pervanadate treatment also led to an increase in overall protein tyrosine phosphorylation and phosphorylation of Stat1, as well as the subsequent increase in ICAM-1 mRNA and cell surface protein levels. These data show that pervanadate can mimic each step in the IFNgamma-mediated pathway leading to ICAM-1 expression, demonstrate the ability of a pharmacologic agent to bypass the standard cytokine-receptor interaction required for increased ICAM-1 expression, and emphasize the importance of protein tyrosine phosphatases and protein tyrosine kinases in mediating inflammatory responses in the skin.
Duff
J L
JL
Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322, U.S.A.
Quinlan
K L
KL
Paxton
L L
LL
Naik
S M
SM
Caughman
S W
SW
D004268:DNA-Binding Proteins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology*; D015603:Keratinocytes / Q000737:chemistry; D008565:Membrane Proteins / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014638:Vanadates / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; C076715:pervanadate; D018799:Intercellular Adhesion Molecule-1; D014638:Vanadates; D007371:Interferon-gamma; D017027:Protein Tyrosine Phosphatases