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

• Verfasst von: Horvatova, Alzbeta [VerfasserIn]
• Verfasst von: Otto, Ann-Christin [VerfasserIn]
• Verfasst von: Zhang, Yuling [VerfasserIn]
• Verfasst von: Gan-Schreier, Hongying [VerfasserIn]
• Verfasst von: Pathil-Warth, Anita [VerfasserIn]
• Verfasst von: Stremmel, Wolfgang [VerfasserIn]
• Verfasst von: Chamulitrat, Walee [VerfasserIn]
• Titel: Ursodeoxycholyl iysophosphatidylethanolamide negatively regulates TLR-mediated lipopolysaccharide response in human THP-1-derived macrophages
• Verf.angabe: Alzbeta Horvatova, Tanyarath Utaipan, Ann-Christin Otto, Yuling Zhang, Hongying Gan-Schreier, Petr Pavek, Anita Pathil, Wolfgang Stremmel, Walee Chamulitrat
• E-Jahr: 2018
• Jahr: 20 February 2018
• Umfang: 12 S.
• Fussnoten: Gesehen am 12.09.2019
• Titel Quelle: Enthalten in: European journal of pharmacology
• Ort Quelle: New York, NY [u.a.] : Elsevier, 1967
• Jahr Quelle: 2018
• Band/Heft Quelle: 825(2018), Seite 63-74
• ISSN Quelle: 1879-0712
• DOI: doi:10.1016/j.ejphar.2018.02.030
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Bile-acid and phospholipid conjugates
• Sach-SW: Cytokines
• Sach-SW: Lipid rafts
• Sach-SW: Lipopolysaccharides
• Sach-SW: Macrophages
• Sach-SW: Signaling pathways
• K10plus-PPN: 1676568735

Abstract

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 24h induced the release of pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. This release was markedly inhibited by pretreatment with UDCA-18:1LPE by ~ 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-κB by ~ 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-κB activation. These conjugates may represent a class of lead compounds for development of anti-inflammatory drugs.