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

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-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.

Horvatova A ，Utaipan T ，Otto AC ，Zhang Y ，Gan-Schreier H ，Pavek P ，Pathil A ，Stremmel W ，Chamulitrat W ... -  《-》

Anti-inflammatory properties of ursodeoxycholyl lysophosphatidylethanolamide in endotoxin-mediated inflammatory liver injury.

Ludwig JM ，Zhang Y ，Chamulitrat W ，Stremmel W ，Pathil A ... -  《PLoS One》

The synthetic bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide suppresses TNFα-induced liver injury.

Excessive apoptosis and leukocyte-dependent inflammation mediated by pro-inflammatory cytokines, such as TNFα, are cardinal features of acute liver injury. This study evaluated the ability of the newly designed bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) to protect from hepatocellular injury in comparison to the known hepatoprotectant ursodeoxycholic acid (UDCA) and phosphatidylcholine (PC). Anti-apoptotic and anti-inflammatory properties of UDCA-LPE were evaluated after TNFα treatment of embryonic human hepatocyte cell line CL48 as well as of primary human hepatocytes. Acute liver injury was induced in C57BL/6 mice with d-galactosamine/lipopolysaccharide (GalN/LPS) in order to determine in vivo efficacy of the conjugate. UDCA-LPE inhibited TNFα-induced apoptosis and inflammation in hepatocytes in vitro and markedly ameliorated GalN/LPS-mediated fulminant hepatitis in mice, whereas UDCA or PC failed to show protection. The conjugate was able to decrease injury-induced elevation of phospholipase A(2) activity as well as its product lysophosphatidylcholine. Analysis of hepatic gene expression showed that UDCA-LPE treatment led to favourable inhibitory effects on expression profiles of key pro-inflammatory cytokines and chemokines, which are crucial for leukocyte recruitment and activation thereby inhibiting chemokine-mediated aggravation of parenchymal damage. Thus, UDCA-LPE as a synthetic bile acid-phospholipid conjugate may represent a potent anti-inflammatory agent that is more effective than UDCA and PC for treatment of liver diseases.

Pathil A ，Warth A ，Chamulitrat W ，Stremmel W ... -  《-》

Anti-inflammatory effects of ursodeoxycholic acid by lipopolysaccharide-stimulated inflammatory responses in RAW 264.7 macrophages.

Ko WK ，Lee SH ，Kim SJ ，Jo MJ ，Kumar H ，Han IB ，Sohn S ... -  《PLoS One》

Bile salt-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide as a hepatoprotective agent.

Chamulitrat W ，Burhenne J ，Rehlen T ，Pathil A ，Stremmel W ... -  《-》