Inhibition of lipopolysaccharide-induced inducible nitric oxide synthase expression by endoplasmic reticulum stress

被引:27
作者
Ho, Hui-Ju [2 ]
Huang, Duen-Yi [2 ]
Ho, Feng-Ming [3 ,4 ]
Lee, Long-Teng [1 ]
Lin, Wan-Wan [2 ,5 ]
机构
[1] Natl Taiwan Univ Hosp, Dept Family Med, Taipei, Taiwan
[2] Natl Taiwan Univ, Dept Pharmacol, Coll Med, Taipei 10764, Taiwan
[3] Tao Yuan Gen Hosp, Dept Hlth Execut Yuan, Dept Internal Med, Tao Yuan, Taiwan
[4] Chung Yuan Christian Univ, Dept Biomed Engn, Tao Yuan, Taiwan
[5] Taipei Med Univ, Grad Inst Med Sci, Taipei, Taiwan
关键词
ER stress; LPS; NF-kappa B; STAT; PTP; UNFOLDED PROTEIN RESPONSE; NF-KAPPA-B; MOUSE PERITONEAL-MACROPHAGES; INNATE IMMUNE-RESPONSES; INTERFERON-GAMMA; GENE-EXPRESSION; IFN-GAMMA; KINASE PHOSPHATASE-1; MAPK PHOSPHATASE-1; ER STRESS;
D O I
10.1016/j.cellsig.2012.07.018
中图分类号
Q2 [细胞生物学];
学科分类号
071013 [干细胞生物学];
摘要
Endoplasmic reticulum (ER) stress is induced in infectious and inflammatory conditions, but its role in inflammatory responses still remains elusive. In this study we found tunicamycin (TM) and brefeldin A (BFA), two ER stressors, could attenuate lipopolysaccharide (LPS)-elicited inducible nitric oxide synthase (iNOS) gene expression in murine RAW264.7 macrophages, and this effect was not resulting from the effects on IKK or MAPKs activation. However, ER stressors could block NF-kappa B binding to the iNOS promoter in late-phase signaling evoked by LPS. Results indicated that inhibition of RelB nuclear translocation and p300 expression are involved in the anti-inflammatory actions of ER stressors. We also found that ER stressors could block LPS- and IFN (alpha, beta, and gamma)-mediated STAT1 phosphorylation. Our results suggest that activation of MKP-1 via a Ca/calmodulin/calcineurin pathway accounts for the inhibitory effect of ER stressors on IFN signaling. MKP-1 was downregulated by IFN-gamma and is a newly identified protein phosphatase targeting STAT1. Taken together, these results indicate that multiple mechanisms are involved in the inhibition of LPS-induced iNOS gene expression by ER stressors. These include downregulation of RelB and p300, upregulation of MKP-1, and inhibition of the JAK/STAT signaling pathway. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:2166 / 2178
页数:13
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