IFN regulatory factor-1 regulates IFN-γ-dependent cathepsin S expression

Karin Storm Van'S Gravesande, Matthew D. Layne, Qiang Ye, Louis Le, Rebecca M. Baron, Mark A. Perrella, Laura Santambrogio, Eric S. Silverman, Richard J. Riese

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Cathepsin S is a cysteine protease with potent endoproteolytic activity and a broad pH profile. Cathepsin S activity is essential for complete processing of the MHC class II-associated invariant chain within B cells and dendritic cells, and may also be important in extracellular matrix degradation in atherosclerosis and emphysema. Unique among cysteine proteases, cathepsin S activity is up-regulated by IFN-γ. Given its importance, we sought to elucidate the pathway by which IFN-γ increases cathepsin S expression. Our data demonstrate that the cathepsin S promoter contains an IFN-stimulated response element (ISRE) that is critical for IFN-γ-induced gene transcription in a cell line derived from type II alveolar epithelial (A549) cells. IFN response factor (IRF)-2 derived from A549 nuclear extracts associates with the ISRE oligonucleotide in gel shift assays, but is quickly replaced by IRF-1 following stimulation with IFN-γ. The time course of IRF-1/ISRE complex formation correlates with increased levels of IRF-1 protein and cathepsin S mRNA. Overexpression of IRF-1, but not IRF-2, markedly augments cathepsin S promoter activity in A549 cells. Furthermore, overexpression of IRF-1 increases endogenous cathepsin S mRNA levels in 293T epithelial cells. Finally, freshly isolated bone marrow cells from IRF-1-1- mice fail to up-regulate cathepsin S activity in response to IFN-γ. Thus, IRF-1 is the critical transcriptional mediator of IFN-γ-dependent cathepsin S activation. These data elucidate a new pathway by which IRF-1 may affect MHC class II processing and presentation.

Original languageEnglish (US)
Pages (from-to)4488-4494
Number of pages7
JournalJournal of Immunology
Volume168
Issue number9
StatePublished - May 1 2002

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Van'S Gravesande, K. S., Layne, M. D., Ye, Q., Le, L., Baron, R. M., Perrella, M. A., Santambrogio, L., Silverman, E. S., & Riese, R. J. (2002). IFN regulatory factor-1 regulates IFN-γ-dependent cathepsin S expression. Journal of Immunology, 168(9), 4488-4494.