Regulation of xanthine dehydrogenase and xanthine oxidase activity and gene expression in cultured rat pulmonary endothelial cells

G. P. Dupont, T. P. Huecksteadt, B. C. Marshall, U. S. Ryan, J. R. Michael, J. R. Hoidal

Research output: Contribution to journalArticlepeer-review

Abstract

The central importance of xanthine dehydrogenase (XDH) and xanthine oxidase (XO) in the pathobiochemistry of a number of clinical disorders underscores the need for a comprehensive understanding of the regulation of their expression. This study was undertaken to examine the effects of cytokines on XDH/XO activity and gene expression in pulmonary endothelial cells. The results indicate that IFN-γ is a potent inducer of XDH/XO activity in rat lung endothelial cells derived from both the microvasculature (LMVC) and the pulmonary artery. In contrast, interferon-α/β, tumor necrosis factor-α, interleukin-1 or -6, lipopolysaccharide and phorbol myristate acetate have no demonstrable effect. The increase in XDH/XO activity requires new protein synthesis. By Northern analysis, IFN-γ markedly increases the level of the 5.0-kb XDH/XO mRNA in LMVC. The increase is due, in part, to increased transcription rate of the XDH/XO gene. Transcriptional activation does not require new protein synthesis. The physiologic relevance of these observations was evaluated by administering IFN-γ to rats. Intraperitoneal administration leads to an increased XDH/XO activity and XDH/XO mRNA level in rat lungs. In sum, IFN-γ is a potent and biologically relevant inducer of XDH/XO expression; the major site of upregulation occurs at the transcriptional level.

Original languageEnglish (US)
Pages (from-to)197-202
Number of pages6
JournalJournal of Clinical Investigation
Volume89
Issue number1
DOIs
StatePublished - 1992
Externally publishedYes

Keywords

  • Interferon gamma
  • Lung microvascular
  • Pulmonary artery

ASJC Scopus subject areas

  • Medicine(all)

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