Methotrexate in Atherogenesis and Cholesterol Metabolism
Figure 2
Abrogation of interferon (IFN)-γ mediated downregulation of adenosine triphosphate binding cassette transporter A1 (ABCA1) by adenosine A3 receptor ligation. IFN-γ binds the IFN receptor and subsequently decreases ABCA1 expression by increasing signal transducer and activator of transcription (STAT) protein activity via tyrosine (Y) and serine (S) phosphorylation. The IFN receptor induces a janus-kinase mediated process which tyrosine phosphorylates STAT. The serine is phosphorylated by a calcium/calmodulin-dependent protein kinase II (CaMKII) activated by a calcium flux initiated by the IFN receptor. These activated STAT proteins dimerize and translocate to the nucleus, where they downregulate liver X receptor (LXR)α. While LXR normally upregulates ABCA1 expression, a decrease in LXR results in a consequent decrease in ABCA1 expression. Significantly, adenosine may counteract the effects of IFN-γ on ABCA1 via the A3 receptor. A3 activation prevents the accumulation of Ca2+ and may thus prevent the activation of CaMKII. This reduced activity will decrease the phosphorylation of S727 on STAT, decreasing STAT activity and thus preventing the downregulation of ABCA1.
