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-Dependent Cathepsin S Expression1
* Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115
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-
. Given its importance, we sought to elucidate the pathway by
which IFN- increases cathepsin S expression. Our data
demonstrate that the cathepsin S promoter contains an IFN-stimulated
response element (ISRE) that is critical for IFN--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-.
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-. Thus,
IRF-1 is the critical transcriptional mediator of IFN--dependent
cathepsin S activation. These data elucidate a new pathway by which
IRF-1 may affect MHC class II processing and
presentation.
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