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The Immunoproteasomes Regulate LPS-Induced TRIF/TRAM Signaling Pathway in Murine Macrophages

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Abstract

We have proposed the novel concept that the macrophage ubiquitin–proteasome pathway functions as a key regulator of Lipopolysaccharide (LPS)-induced inflammation signaling. These findings suggest that proteasome-associated protease subunits X, Y, and Z are replaced by LMP subunits after LPS treatment of RAW 264.7 cells. The objective here was to determine the contribution of selective LMP proteasomal subunits to LPS-induced nitric oxide (NO) and TNF-α production in primary murine macrophages. Accordingly, thioglycollate-elicited macrophages from LMP7, LMP2, LMP10 (MECL-1), and LMP7/MECL-1 double knockout mice were stimulated in vitro with LPS, and were found to generate markedly reduced NO levels compared to wild-type (WT) mice, whereas TNF-α levels responses were essentially unaltered relative to wild-type responses. The recent studies suggest that the TRIF/TRAM pathway is defective in LMP knockouts which may explain why iNOS/NO are not robustly induced in LPS-treated macrophages from knockouts. Treating these macrophages with IFN-γ and LPS, however, reverses this defect, leading to robust NO induction. TNF-α is induced by LPS in the LMP knockout macrophages because IκB and IRAK are degraded normally via the MyD88 pathway. Collectively, these findings strongly support the concept that LMP7/MECL-1 proteasomes subunits actively function to regulate LPS-induced NO production by affecting the TRIF/TRAM pathway.

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Acknowledgments

These studies were supported in part by NIH grants GM-50870 (NQ), and AI-18797 (SNV). We thank Drs. Alfred L. Goldberg and Alexei Kisselev for helpful suggestions. Jing Shen is now with the WA Dental group, Bellevue, Washington.

Disclosures

The authors have no financial conflict of interest.

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Authors and Affiliations

  1. Department of Basic Medical Science, School of Medicine, Shock/Trauma Research Center, University of Missouri, Kansas City, MO, 64108, USA

    Julia Reis, Ferdaus Hassan, Xiu Qin Guan, Jing Shen, Christopher J. Papasian, Asaf A. Qureshi, David C. Morrison & Nilofer Qureshi

  2. Department of Surgery, Shock/Trauma Research Center, University of Missouri, Kansas City, MO, 64108, USA

    Charles W. Van Way III

  3. Department of Pharmacology and Toxicology, School of Pharmacy, University of Missouri, Kansas City, MO, 64108, USA

    Julia Reis & Nilofer Qureshi

  4. Department of Molecular Genetics, University of Cincinnati Medical Center, Cincinnati, OH, 45267-0524, USA

    John J. Monaco

  5. Department of Microbiology and Immunology, University of Maryland, Baltimore, MD, 21201, USA

    Stefanie N. Vogel

  6. Department of Basic Medical Science, School of Medicine, Shock/Trauma Research Center, University of Missouri, 2411 Holmes Street, Kansas City, MO, 64108, USA

    Nilofer Qureshi

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  1. Julia Reis
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  2. Ferdaus Hassan
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Correspondence to Nilofer Qureshi.

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Reis, J., Hassan, F., Guan, X.Q. et al. The Immunoproteasomes Regulate LPS-Induced TRIF/TRAM Signaling Pathway in Murine Macrophages. Cell Biochem Biophys 60, 119–126 (2011). https://doi.org/10.1007/s12013-011-9183-7

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  • DOI: https://doi.org/10.1007/s12013-011-9183-7

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