Ursodeoxycholyl lysophosphatidylethanolamide negatively regulates TLR-mediated lipopolysaccharide response in human THP-1-derived macrophages

被引：4

作者：

Horvatova, Alzbeta ^{[1
,2
]}

Utaipan, Tanyarath ^{[3
]}

Otto, Ann-Christin ^{[1
]}

Zhang, Yuling ^{[1
]}

Gan-Schreier, Hongying ^{[1
]}

Pavek, Petr ^{[2
]}

Pathil, Anita ^{[1
]}

Stremmel, Wolfgang ^{[1
]}

Chamulitrat, Walee ^{[1
]}

机构：

[1] Heidelberg Univ, Dept Internal Med 4, Neuenheimer Feld 410, D-69120 Heidelberg, Germany

[2] Charles Univ Prague, Fac Pharm, Dept Pharmacol & Toxicol, Heyorovskeho 1203, Hradec Kralove 50005, Czech Republic

[3] Prince Songkla Univ, Fac Sci & Technol, Dept Preclin, Pattani Campus, Pattani 94000, Thailand

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2018年 / 825卷

关键词：

Bile-acid and phospholipid conjugates; Cytokines; Macrophages; Lipopolysaccharides; Signaling pathways; Lipid rafts; NF-KAPPA-B; LIPID RAFTS; SIGNAL-TRANSDUCTION; IMMUNE-SYSTEM; MEMBRANE-COMPOSITION; CHRONIC DISEASES; FATTY-ACIDS; BILE-ACIDS; RECEPTOR; CELLS;

D O I：

10.1016/j.ejphar.2018.02.030

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The bile acid-phospholipid conjugate ursodeoxycholyl oleoyl-lysophophatidylethanolamide (UDCA-18:1LPE) is an anti-inflammatory and anti-fibrotic agent as previously shown in cultured hepatocytes and hepatic stellate cells as well as in in vivo models of liver injury. We hypothesize that UDCA-18:1LPE may directly inhibit the activation of immune cells. We found that UDCA-18:1LPE was capable of inhibiting the migration of phorbol ester-differentiated human THP-1 cells. We examined anti-inflammatory activity of UDCA-18:1LPE during activation of THP1-derived macrophages. Treatment of these macrophages by bacterial lipopolysaccharide (LPS) for 24 h induced the release of pro-inflammatory cytokines TNF-alpha, IL-6 and IL-1 beta. This release was markedly inhibited by pretreatment with UDCA-18:1LPE by similar to 65-90%. Derivatives with a different fatty-acid chain in LPE moiety also exhibited anti-inflammatory property. Western blotting and indirect immunofluorescence analyses revealed that UDCA-18:1LPE attenuated the expression of phosphorylated p38, MKK4/MKK7, JNK1/2, and c-Jun as well as nuclear translocation of NF-kappa B by similar to 22-86%. After LPS stimulation, the Toll-like receptor adaptor proteins, myeloid differentiation factor 88 and TNF receptor associated factor 6, were recruited into lipid rafts and UDCA-18:1LPE inhibited this recruitment by 22% and 58%, respectively. Moreover, LPS treatment caused a decrease of the known cytoprotective lysophosphatidylcholine species containing polyunsaturated fatty acids by 43%, and UDCA-18:1LPE co-treatment reversed this decrease. In conclusion, UDCA-18:1LPE and derivatives inhibited LPS inflammatory response by interfering with Toll-like receptor signaling in lipid rafts leading to an inhibition of MAPK and NF-kappa B activation. These conjugates may represent a class of lead compounds for development of anti-inflammatory drugs.

引用

页码：63 / 74

页数：12

共 62 条

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