Tristetraprolin-dependent Post-transcriptional Regulation of Inflammatory Cytokine mRNA Expression by Apolipoprotein A-I

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)-␣, 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-␣ 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 ATPbinding 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.

Interleukin-6 Protects Human Macrophages from Cellular Cholesterol Accumulation and Attenuates the Proinflammatory Response

“…Silencing of ABCA1 expression in human macrophages indicates that only the action of IL-6 on IL-1␤ secretion may be dependent on ABCA1 as this latter was abolished in ABCA1 KD macrophages. Previous studies described ABCA1 as an antiinflammatory receptor through the interaction of apoAI with ABCA1 and subsequent activation of the Jak2/Stat-3 signaling pathway (13,14). Although human macrophages do not express apoAI, such an effect occurs in vitro when THP-1 macrophages are incubated in the presence of apoAI (14).…”

“…Although human macrophages do not express apoAI, such an effect occurs in vitro when THP-1 macrophages are incubated in the presence of apoAI (14). Thus, the addition of exogenous apoAI to THP-1 macrophages strongly attenuated the stimulation of proinflammatory cytokines secretion, such as IL-1␤, observed upon LPS treatment (14). The requirement of ABCA1 in the inhibitory effect of IL-6 on IL-1␤ secretion may, therefore, result from the induction of ABCA1 expression by IL-6 in THP-1 macrophages, which would favor interaction of ABCA1 not with apoAI, which was not present in our experimental conditions, but potentially with apoE, which is abundantly expressed by human macrophages and was largely described to interact with ABCA1 for promoting cellular cholesterol efflux.…”

“…Previous studies described ABCA1 as an antiinflammatory receptor through the interaction of apoAI with ABCA1 and subsequent activation of the Jak2/Stat-3 signaling pathway (13,14). Although human macrophages do not express apoAI, such an effect occurs in vitro when THP-1 macrophages are incubated in the presence of apoAI (14). Thus, the addition of exogenous apoAI to THP-1 macrophages strongly attenuated the stimulation of proinflammatory cytokines secretion, such as IL-1␤, observed upon LPS treatment (14).…”

“…Reciprocally, activation of Toll-like receptors 3 and 4 inhibits the induction of LXR target genes, such as ABCA1, in macrophages and strongly reduces cholesterol efflux (12). Although those studies suggest that the inflammatory property of ABCA1 results from its ability to modulate free cholesterol levels and distribution in plasma membrane, recent studies propose that macrophage ABCA1 may act as an antiinflammatory receptor through activation of Jak2/Stat3 pathway after apoAI binding (13,14).…”

Tristetraprolin: a novel mediator of the anticancer properties of resveratrol

“…The expression, phosphorylation, and subcellular localization of TTP, together with interactions of TTP with other proteins, are closely related to the occurrence and development of malignant tumors, suggesting that TTP expression and dysfunction are an important indicator of cancer development (Sanduja et al, 2012). The expression of TTP can be induced by many factors, including insulin (Cao et al, 2008), mitogen (Hitti et al, 2006), apolipoprotein (Yin et al, 2011), and green tea (Cao et al, 2007). The upregulation of TTP has been found to inhibit the development of inflammation, atherosclerosis, and some malignancies (Yin et al, 2009).…”