TNF-α-induced self expression in human lung endothelial cells is inhibited by native and oxidized α1-antitrypsin

Devipriya Subramaniyam, Robert Virtala, Krzysztof Pawłowski, Ib Groth Clausen, S. Warkentin, Tim Stevens, Sabina Janciauskiene

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Endothelial cells are among the main physiological targets of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). In endothelial cells TNF-α elicits a broad spectrum of biological effects including differentiation, proliferation and apoptosis. α1-antitrypsin (AAT), an endogenous inhibitor of serine proteases plays a vital role in protecting host tissue from proteolytic injury at sites of inflammation. Recently, it has been shown that AAT can be internalized by pulmonary endothelial cells, raising speculation that it may modulate endothelial cell function in addition to suppressing protease activity. Using Affymetrix microarray technology, real time PCR and ELISA methods we have investigated the effects of AAT on un-stimulated and TNF-α stimulated human primary lung microvascular endothelial cell gene expression and protein secretion. We find that AAT and TNF-α generally induced expression of distinct gene families with AAT exhibiting little activity in terms of inflammatory gene expression. Approximately 25% of genes up regulated by TNF-α were inhibited by co-administration of AAT including TNF-α-induced self expression. Surprisingly, the effects of AAT on TNF-α-induced self expression was inhibited equally well by oxidized AAT, a modified form of AAT, which lacks serine protease inhibitor activity. Overall, the pattern of gene expression regulated by native and oxidized AAT was similar with neither inducing pro-inflammatory gene expression. These findings suggest that inhibitory effects of native and oxidized forms of AAT on TNF-α stimulated gene expression may play an important role in limiting the uncontrolled endothelial cell activation and vascular injury in inflammatory disease.

Original languageEnglish (US)
Pages (from-to)258-271
Number of pages14
JournalInternational Journal of Biochemistry and Cell Biology
Volume40
Issue number2
DOIs
StatePublished - 2008
Externally publishedYes

Keywords

  • Affymetrix microarray technology
  • Inflammation
  • Lung microvascular endothelial cells
  • Oxidized
  • α1-Antitrypsin

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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