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

作者：Reis Julia; Hassan Ferdaus; Guan Xiu Qin; Shen Jing; Monaco John J; Papasian Christopher J; Qureshi Asaf A; Van Way Charles W III; Vogel Stefanie N; Morrison David C; Qureshi Nilofer^*

来源：Cell Biochemistry and Biophysics, 2011, 60(1-2): 119-126.

DOI：10.1007/s12013-011-9183-7

• Inflammation
• Endotoxic shock
• Macrophages
• Cytokines
• Nitric oxide

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-alpha 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-alpha 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-gamma and LPS, however, reverses this defect, leading to robust NO induction. TNF-alpha is induced by LPS in the LMP knockout macrophages because I kappa B 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.

• 出版日期2011-6