Glucose regulated protein 78 prompts scavenger receptor A-mediated secretion of tumor necrosis factor-α by RAW 264.7 cells.

Abstract

1. Activation of macrophages plays an important role in atherosclerosis. In order to investigate the effect of endoplasmic reticulum (ER) stress on cytokine release from macrophages, the RAW264.7 mouse macrophage cell line was treated with 0.2 mmol/L 6-aminonicotinamide (6-AN) for 36 h and the secretion of tumour necrosis factor (TNF)-α determined. In addition, Raw 264.7 cells were incubated in the presence of 10 μg/mL acetylated low-density lipoprotein (acLDL) at 37 °C for 8 h. 2. Secretion of TNF-α from RAW264.7 cells was stimulated by both loading of cells with acLDL and following 6-AN treatment. In addition, the expression of glucose-regulated protein (GRP) 78 was increased in 6-AN-treated cells (by 165%). 3. In separate experiments, PD98059, a specific inhibitor of the mitogen-activated protein kinase kinase (MEK) pathway, blocked acLDL- and/or 6-AN-induced TNF-α secretion, whereas LY294002, which blocks the AKT signalling pathway, had no effect. On the basis of these results, we speculate that acLDL/6-AN-induced secretion of TNF-α from RAW264.7 cells may be regulated by activation of the MEK signalling pathway. 4. The present study suggests that the accumulation of lipids in cells and/or ER stress could lead to macrophage apoptosis as a result of the increased production of TNF-α, which integrates into atherosclerosis.

• Authors: Song Gao, Xiaozheng Zhong, Jingjing Ben, Xudong Zhu, Yuan Zheng, Yan Zhuang, Hui Bai, Li Jiang, Yaoyu Chen, Yong Ji, Qi Chen
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 36 Issue 9 Pg. 940-4 (Sep 2009) ISSN: 1440-1681 [Electronic] Australia
• PMID: 19473344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromones
• Endoplasmic Reticulum Chaperone BiP
• Flavonoids
• Heat-Shock Proteins
• Lipoproteins, LDL
• Morpholines
• Msr1 protein, mouse
• Protein Kinase Inhibitors
• Scavenger Receptors, Class A
• Tumor Necrosis Factor-alpha
• acetyl-LDL
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• 6-Aminonicotinamide
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• 6-Aminonicotinamide (pharmacology)
• Animals
• Cell Line
• Chromones (pharmacology)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress
• Flavonoids (pharmacology)
• Heat-Shock Proteins (metabolism)
• Lipoproteins, LDL (metabolism)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• Macrophages (drug effects, immunology, metabolism)
• Mice
• Morpholines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Scavenger Receptors, Class A (metabolism)
• Signal Transduction
• Time Factors
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation