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The Journal of Immunology, 2002, 169: 3046-3052.
Copyright © 2002 by The American Association of Immunologists

Regulation of Immunoproteasome Subunit Expression In Vivo Following Pathogenic Fungal Infection1

Lance F. Barton*, Miguel Cruz*,§, Reshma Rangwala*, George S. Deepe, Jr.{ddagger} and John J. Monaco2,*,{dagger}

* Department of Molecular Genetics, Biochemistry, and Microbiology, {dagger} Howard Hughes Medical Institute, and {ddagger} Division of Infectious Diseases, Department of Medicine, University of Cincinnati, Cincinnati, OH 45267; and § Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico

The proteasome catalytic {beta} subunits LMP2, LMP7, and MECL-1 and two proteasome activator proteins, PA28 {alpha} and {beta}, are induced following exposure to IFN-{gamma} in vitro. Induction of these immunosubunits and the PA28 {alpha}/{beta} hetero-oligomer alters proteasome catalytic functions and specificity and enhances production of certain MHC class I epitopes. We sought to determine whether and to what extent proteasome subunit composition is regulated in vivo and to elucidate the mechanisms of such regulation. We analyzed basal expression levels of these inducible genes in normal, IFN-{gamma}-deficient, and Stat-1-deficient mice. Mice of all three genotypes display constitutive expression of the immunosubunits and PA28, demonstrating that basal expression in vivo is independent of endogenous IFN-{gamma} production. However, basal expression levels are reduced in Stat-1-/- mice, demonstrating a role for Stat-1 independent of IFN-{gamma} signaling. To demonstrate that IFN-{gamma} can induce these genes in vivo, mice were infected with Histoplasma capsulatum. Elevated expression of these genes followed the same time course as IFN-{gamma} expression in infected mice. IFN-{gamma}-deficient mice did not display elevated protein expression following infection, suggesting that other inflammatory cytokines produced in infected mice are unable to influence proteasome expression. Cytokines other than IFN-{gamma} also failed to influence proteasome gene expression in vitro in cell lines that had no basal expression of LMP2, LMP7, or MECL-1. Thus, both in vitro and in vivo data demonstrate that IFN-{gamma} is essential for up-regulation, but not constitutive expression, of immunoproteasome subunits in mice.




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