OxLDL inhibits LPS-induced IFN尾 expression by Pellino3- and IRAK1/4-dependent modification of TANK

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• 作者：Nico Tzieply^a ; Anne-Marie Kuhn^a ; Daniel Morbitzer^a ; Dmitry Namgaladze^a ; Annika Heeg^a ; Liliana Schaefer^b ; Andreas von Knethen^a ; Liselotte E. Jensen^c ; Bernhard Brü ; ne^a ; ^{bruene@pathobiochemie1.de}
• 关键词：hM桅 ; human monocyte derived macrophages ; IFN尾 ; interferon 尾 ; IKK蔚 ; inhibitor of NF魏B kinase 蔚 ; IRAK ; interleukin-1 receptor-associated kinase ; IRF3 ; interferon regulatory factor 3 ; IP-10 ; interferon-inducible protein-10 ; LPS ; lipopolysaccharide ; MAP
• 刊名：Cellular Signalling
• 出版年：2012
• 期刊代码：42_08986568
• 类别：bio
• 出版时间：June, 2012
• 卷：24
• 期：6
• 页码：1141-1149
• 文件大小：944 K

摘要

In atherosclerosis macrophages contribute to disease progression. After infiltrating atherosclerotic lesions they accumulate oxLDL (oxidized low density lipoproteins) and differentiate into foam cells. During this process inhibition of TLR4 (Toll-like receptor 4)-dependent IFN尾 expression occurs. To understand molecular mechanisms how oxLDL inhibits LPS-induced IFN尾 expression in macrophage-derived foam cells, we analyzed the impact of oxLDL on signaling pathways upstream of IFN尾 expression. We identified mono-ubiquitination of TANK (TRAF family member-associated NF魏B activator), a scaffold protein of the TRIF (TIR-domain-containing adapter-inducing IFN尾)-dependent TLR4-signaling cascade. Modified TANK inhibits recruitment of TBK1 (TANK-binding kinase 1) to TRAF3 (TNF receptor associated factor 3) and the subsequent activation of the transcription factor IRF3 (interferon regulatory factor 3). OxLDL stimulates TANK mono-ubiquitination by subsequent activation of IRAK1/4 (interleukin-1 receptor-associated kinases 1 and 4) and Pellino3 downstream of SR-A1 (scavenger receptor-A1). Our observations highlight the regulatory impact of IRAK1/4 and Pellino3 on the TRIF-dependent TLR4-signaling cascade, which might be of general importance for disease conditions associated with macrophage pathologies such as atherosclerosis.