title: The immunoproteasomes regulate LPS-induced TRIF/TRAM signaling pathway in murine macrophages.
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.
authors: Department of Basic Medical Science, School of Medicine, Shock/Trauma Research Center, University of Missouri, Kansas City, MO 64108, USA.
authors: Julia
authors: J
authors: Reis
authors: Ferdaus
authors: F
authors: Hassan
authors: Xiu Qin
authors: XQ
authors: Guan
authors: Jing
authors: J
authors: Shen
authors: John J
authors: JJ
authors: Monaco
authors: Christopher J
authors: CJ
authors: Papasian
authors: Asaf A
authors: AA
authors: Qureshi
authors: Charles W
authors: CW
authors: Van Way
authors: Stefanie N
authors: SN
authors: Vogel
authors: David C
authors: DC
authors: Morrison
authors: Nilofer
authors: N
authors: Qureshi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003546:Cysteine Endopeptidases; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D046988:Proteasome Endopeptidase Complex; D018123:Receptors, Interleukin; D014409:Tumor Necrosis Factor-alpha; C476286:Ticam1 protein, mouse; C480228:TICAM2 protein, human; C476416:Ticam2 protein, mouse; C071313:LMP-2 protein; C077436:LMP7 protein; C490920:Psmb10 protein, mouse