PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages

2018 ◽  
Vol 114 (8) ◽  
pp. 1145-1153 ◽  
Author(s):  
Zufeng Ding ◽  
Shijie Liu ◽  
Xianwei Wang ◽  
Sue Theus ◽  
Xiaoyan Deng ◽  
...  
Keyword(s):  
Peritoneal Macrophages ◽  
Scavenger Receptors ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Ldl Uptake ◽  
Factor Alpha ◽  
Pcsk9 Inhibition ◽  
Inflammatory Milieu ◽  
Mouse Peritoneal Macrophages ◽  
Necrosis Factor

Abstract Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to influence macrophage biology and modulate atherogenesis. We conducted this study to examine the regulation of scavenger receptors (SRs) (LOX-1, SRA, and CD36) and oxidized liporoptein cholesterol (ox-LDL) uptake in macrophages by PCSK9. Methods and results Treatment of mouse peritoneal macrophages with tumour necrosis factor alpha (TNF-α) resulted in concentration-dependent modest, but significant, increase in PCSK9 expression. Importantly, treatment of TNF-α primed macrophages with recombinant murine PCSK9 increased the expression of LOX-1, SRA, and CD36 2-5 fold, and enhanced ox-LDL uptake by ≈five-fold. The increase in LOX-1 was much greater than in SRA or CD36. PCSK9 inhibition (by siRNA transfection or use of macrophages from PCSK9−/− mice) reduced the expression of SRs (LOX-1 ≫ SRA or CD36). Ox-LDL uptake in response to PCSK9 was also inhibited in macrophages from LOX-1−/− mice (P < 0.05 vs. macrophages from SRA−/− and CD36−/− mice). Upregulation of PCSK9 by cDNA transfection induced intense ox-LDL uptake which was inhibited by co-transfection of cells with siRNA LOX-1 (P < 0.05 vs. siRNA SRA or siRNA CD36). Further, TNF-α-mediated PCSK9 upregulation and subsequent expression of SRs and ox-LDL uptake were reduced in macrophages from gp91phox−/−, p47phox−/− and p22phox−/− mice (vs. macrophages from wild-type mice). Conclusions This study shows that in an inflammatory milieu, elevated levels of PCSK9 potently stimulate the expression of SRs (principally LOX-1) and ox-LDL uptake in macrophages, and thus contribute to the process of atherogenesis.

scholarly journals Lipopolysaccharide-induced selective priming effects on tumor necrosis factor alpha and nitric oxide production in mouse peritoneal macrophages.

1993 ◽  
Vol 177 (2) ◽  
pp. 511-516 ◽  
Author(s):  
X Zhang ◽  
D C Morrison
Keyword(s):  
Tumor Necrosis ◽  
Peritoneal Macrophages ◽  
Tnf Alpha ◽  
No Production ◽  
Necrosis Factor Alpha ◽  
Priming Effects ◽  
Alpha Production ◽  
Factor Alpha ◽  
Mouse Peritoneal Macrophages ◽  
Necrosis Factor

Preculture of thioglycollate-elicited C3HeB/FeJ mouse peritoneal macrophages in vitro with subthreshold stimulatory concentrations of lipopolysaccharide (LPS) can induce hyporesponsiveness (desensitization) to both tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) production when these cells are subsequently stimulated with 100 ng/ml of LPS. We have established, however, that the primary dose of LPS required for inducing downregulation of NO production is significantly lower than that required for inducing downregulation of TNF-alpha production. Further, when LPS-pretreated macrophages become refractory to subsequent LPS stimulation for NO production, the secondary LPS-stimulated TNF-alpha production is markedly enhanced, and vice versa. These results indicate that LPS-induced TNF-alpha and NO production by macrophages are differentially regulated, and that the observed desensitization process may not reflect a state in which macrophages are totally refractory to subsequent LPS stimulation. Rather, our data suggest that LPS-pretreated macrophages become selectively primed for differential responses to LPS. The LPS-induced selective priming effects are not restricted to LPS stimulation, but extend as well to stimuli such as zymosan, Staphylococcus aureus, and heat-killed Listeria monocytogenes.

scholarly journals Clindamycin Modulates Inflammatory-Cytokine Induction in Lipopolysaccharide-Stimulated Mouse Peritoneal Macrophages

2003 ◽  
Vol 47 (1) ◽  
pp. 363-367 ◽  
Author(s):  
Tetsuji Nakano ◽  
Kazufumi Hiramatsu ◽  
Kenji Kishi ◽  
Norio Hirata ◽  
Jun-ichi Kadota ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Peritoneal Macrophages ◽  
Cytokine Mrna ◽  
Necrosis Factor Alpha ◽  
Expression Levels ◽  
Cytokine Induction ◽  
Intracellular Expression ◽  
Factor Alpha ◽  
Mouse Peritoneal Macrophages ◽  
Necrosis Factor

ABSTRACT We investigated the mechanism by which clindamycin (CLI) modulates cytokine induction after lipopolysaccharide (LPS) stimulation. Although CLI decreased the intracellular expression levels of tumor necrosis factor alpha and interleukin 1β (IL-1β) and increased IL-6 expression in macrophages, cytokine mRNA expression levels were similar in CLI-treated and untreated groups. Our findings suggest that CLI modulates cytokine production in LPS-stimulated macrophages.

scholarly journals Recombinant Guinea Pig Tumor Necrosis Factor Alpha Stimulates the Expression of Interleukin-12 and the Inhibition of Mycobacterium tuberculosis Growth in Macrophages

2005 ◽  
Vol 73 (3) ◽  
pp. 1367-1376 ◽  
Author(s):  
Hyosun Cho ◽  
Todd M. Lasco ◽  
Shannon Sedberry Allen ◽  
Teizo Yoshimura ◽  
David N. McMurray
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Tumor Necrosis ◽  
Peritoneal Macrophages ◽  
Interleukin 12 ◽  
Mrna Levels ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF-α) plays an important role in the host immune response to infection with the intracellular pathogen Mycobacterium tuberculosis. It is essential for the formation of protective tuberculous granulomas and regulates the expression of other cytokines which contribute to a protective immune response. Interleukin-12 (IL-12) is known to promote a Th1 response, which is essential for antimycobacterial resistance. Recombinant guinea pig TNF-α (rgpTNF-α) protein (17 kDa) was purified, and its bioactivity was confirmed by its cytotoxicity for L929 fibroblasts. High titers of polyclonal anti-gpTNF-α antibody were obtained by immunization of rabbits. Resident alveolar and peritoneal macrophages were isolated from guinea pigs and infected with either the H37Ra or H37Rv strain of M. tuberculosis. The mRNA levels for TNF-α and IL-12 p40 were measured using real-time PCR. IL-12 p40 mRNA was up-regulated in a dose-dependent manner by rgpTNF-α alone. In infected macrophages, a lower dose of rgpTNF-α intensified the mRNA levels of TNF-α and IL-12 p40. However, higher doses of rgpTNF-α suppressed TNF-α and IL-12 p40 mRNA. The antimycobacterial activity of macrophages was assessed by metabolic labeling of M. tuberculosis with [3H]uracil. Resident alveolar and peritoneal macrophages treated with anti-gpTNF-α antibody to block endogenous TNF-α exhibited increased intracellular mycobacterial growth. These data suggest that the dose of TNF-α is crucial to the stimulation of optimal expression of protective cytokines and that TNF-α contributes to the control of mycobacterial replication to promote host resistance against M. tuberculosis.

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