IFN regulatory factor-1 regulates IFN-gamma-dependent cathepsin S expression.
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.
Storm van's Gravesande
Karin
K
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Layne
Matthew D
MD
Ye
Qiang
Q
Le
Louis
L
Baron
Rebecca M
RM
Perrella
Mark A
MA
Santambrogio
Laura
L
Silverman
Eric S
ES
Riese
Richard J
RJ
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
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