title: Tristetraprolin-dependent post-transcriptional regulation of inflammatory cytokine mRNA expression by apolipoprotein A-I: role of ATP-binding membrane cassette transporter A1 and signal transducer and activator of transcription 3.
abstract: Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the arterial intima. The activated macrophages secreted more pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, which promote the development of the disease. Apolipoprotein A-I (apoA-I), the major component of high density lipoprotein, is involved in reverse cholesterol transport of lipid metabolism. Recently, it has been found that apoA-I suppresses inflammation via repression of inflammatory cytokine expression; the mechanisms of the apoA-I-suppressive action, however, are not yet well characterized. In this study, we have for the first time found that apoA-I suppresses the expression of some inflammatory cytokines induced by lipopolysaccharide via a specific post-transcriptional regulation process, namely mRNA destabilization, in macrophages. Our further studies have also shown that AU-rich elements in the 3'-untranslated region of TNF-α mRNA are responsive to the apoA-I-mediated mRNA destabilization. The apoA-I-induced inflammatory cytokine mRNA destabilization was associated with increased expression of mRNA-destabilizing protein tristetraprolin through a JAK2/STAT3 signaling pathway-dependent manner. When blocking interaction of apoA-I with ATP-binding membrane cassette transporter A1 (ABCA1), a major receptor for apoA-I in macrophages, it would almost totally abolish the effect of apoA-I on tristetraprolin expression. These results present not only a novel mechanism for the apoA-I-mediated inflammation suppression in macrophages but also provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis.
authors.affiliation: Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, 421001, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Yin
authors.forename: Xiang
authors.initials: X
authors.lastname: Deng
authors.forename: Zhong-Cheng
authors.initials: ZC
authors.lastname: Mo
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Zhao
authors.forename: Jin
authors.initials: J
authors.lastname: Jiang
authors.forename: Li-Bao
authors.initials: LB
authors.lastname: Cui
authors.forename: Chun-Zhi
authors.initials: CZ
authors.lastname: Tan
authors.forename: Ge-Bo
authors.initials: GB
authors.lastname: Wen
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.forename: Chao-Ke
authors.initials: CK
authors.lastname: Tang
mesh_terms: D020413:3' Untranslated Regions; D000255:Adenosine Triphosphate / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000378:metabolism*; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D051816:Tristetraprolin / Q000494:pharmacology*
chemical_list: D020413:3' Untranslated Regions; D016632:Apolipoprotein A-I; D016207:Cytokines; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051816:Tristetraprolin; D000255:Adenosine Triphosphate; D002784:Cholesterol; C499076:ATP1A1 protein, human; D000254:Sodium-Potassium-Exchanging ATPase