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

• Published in: Cell biochemistry and biophysics 2011-06, Vol.60 (1-2), p.119-126
• Main Authors: Reis, Julia, Hassan, Ferdaus, Guan, Xiu Qin, Shen, Jing, Monaco, John J., Papasian, Christopher J., Qureshi, Asaf A., Van Way, Charles W., Vogel, Stefanie N., Morrison, David C., Qureshi, Nilofer
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Biochemistry; Biological and Medical Physics; Biomedical and Life Sciences; Biophysics; Biotechnology; Blotting, Western; Cell Biology; Cells, Cultured; Cysteine Endopeptidases - genetics; Cysteine Endopeptidases - metabolism; Female; gamma -Interferon; Inflammation; Inflammation Mediators - metabolism; Interleukin-1 - genetics; Interleukin-1 - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MyD88 protein; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Original Paper; Pharmacology/Toxicology; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; proteasomes; Proteinase; Receptors, Interleukin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal transduction; Signal Transduction - drug effects; Tumor necrosis factor- alpha; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Ubiquitin
• ISSN: 1085-9195; 1559-0283
• DOI: 10.1007/s12013-011-9183-7

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.