title: IFN regulatory factor-1 regulates IFN-gamma-dependent cathepsin S expression.
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-gamma. Given its importance, we sought to elucidate the pathway by which IFN-gamma increases cathepsin S expression. Our data demonstrate that the cathepsin S promoter contains an IFN-stimulated response element (ISRE) that is critical for IFN-gamma-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-gamma. 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(-/-) mice fail to up-regulate cathepsin S activity in response to IFN-gamma. Thus, IRF-1 is the critical transcriptional mediator of IFN-gamma-dependent cathepsin S activation. These data elucidate a new pathway by which IRF-1 may affect MHC class II processing and presentation.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Storm van's Gravesande
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Layne
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ye
authors.forename: Louis
authors.initials: L
authors.lastname: Le
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Baron
authors.forename: Mark A
authors.initials: MA
authors.lastname: Perrella
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.forename: Eric S
authors.initials: ES
authors.lastname: Silverman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Riese
mesh_terms: D001665:Binding Sites; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology; D002403:Cathepsins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000494:pharmacology*; D007700:Kinetics; D010750:Phosphoproteins / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins; D020218:Response Elements; D014157:Transcription Factors; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D010750:Phosphoproteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S