The Journal of Experimental Medicine
Keystone Symposia
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Published online 13 January 2003 doi:10.1084/jem.20020978
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© Rockefeller University Press, 0022-1007/2003/1/169 $5.00
The Journal of Experimental Medicine, Volume 197, Number 2, 169-179

Differential Regulation of Cathepsin S and Cathepsin L in Interferon {gamma}–treated Macrophages

Courtney Beers1, Karen Honey1,2, Susan Fink3, Katherine Forbush1,2 and Alexander Rudensky1,2

1 Department of Immunology, University of Washington, Seattle, WA 98195
2 Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195
3 School of Medicine, University of Washington, Seattle, WA 98195

Address correspondence to Alexander Rudensky, Department of Immunology, University of Washington, UW I 604 J, 1959 NE Pacific Street, Seattle, WA 98195. Phone: 206-685-9310; Fax: 206-685-3612; E-mail: aruden{at}u.washington.edu

Cathepsin S (catS) and cathepsin L (catL) mediate late stages of invariant chain (Ii) degradation in discrete antigen-presenting cell types. Macrophages (M{phi}s) are unique in that they express both proteases and here we sought to determine the relative contribution of each enzyme. We observe that catL plays no significant role in Ii cleavage in interferon (IFN)-{gamma}–stimulated M{phi}s. In addition, our studies show that the level of catL activity is significantly decreased in M{phi}s cultured in the presence of IFN-{gamma} whereas catS activity increases. The decrease in catL activity upon cytokine treatment occurs despite the persistence of high levels of mature catL protein, suggesting that a specific inhibitor of the enzyme is up-regulated in IFN-{gamma}–stimulated peritoneal M{phi}s. Similar inhibition of activity is observed in dendritic cells engineered to overexpress catL. Such enzymatic inhibition in M{phi}s exhibits only partial dependence upon Ii and therefore, other mechanisms of catL inhibition are regulated by IFN-{gamma}. Thus, during a T helper cell type 1 immune response catL inhibition in M{phi}s results in preferential usage of catS, such that major histocompatibility complex class II presentation by all bone marrow–derived antigen-presenting cell is regulated by catS.

Key Words: cathepsin • macrophage • Ii processing • IFN-{gamma} • p41


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