Casein kinase 2 (CK2) is a highly conserved serine-threonine kinase that uses both adenosine triphosphate and guanosine triphosphate as phosphate donors. This constitutively active and ubiquitously expressed enzyme is often present as a tetrameric holoenzyme complex of two catalytic subunits (alpha and/or alpha') and two regulatory beta subunits. The enzyme is known to phosphorylate more than 300 substrates and controls a wide range of processes, including the regulation of cell cycle, apoptosis, transformation, and circadian rhythm. Several lines of recent evidence also suggest a potentially important role for CK2 in the control of the inflammatory response. This review will give an overview of CK2 and its regulation and describe the evidence implicating its role in inflammation.

TNF-like protein 1A (TL1A), a TNF superfamily cytokine that binds to death receptor 3 (DR3), is highly expressed in macrophage foam cell-rich regions of atherosclerotic plaques, although its role in foam cell formation has yet to be elucidated. We investigated whether TL1A can directly stimulate macrophage foam cell formation in both THP-1 and primary human monocyte-derived macrophages with the underlying mechanisms involved. We demonstrated that TL1A promotes foam cell formation in human macrophages in vitro by increasing both acetylated and oxidized low-density lipoprotein uptake, by enhancing intracellular total and esterified cholesterol levels and reducing cholesterol efflux. This imbalance in cholesterol homeostasis is orchestrated by TL1A-mediated changes in the mRNA and protein expression of several genes implicated in the uptake and efflux of cholesterol, such as scavenger receptor A and ATP-binding cassette transporter A1. Furthermore, through the use of virally delivered DR3 short-hairpin RNA and bone marrow-derived macrophages from DR3 knockout mice, we demonstrate that DR3 can regulate foam cell formation and contributes significantly to the action of TL1A in this process in vitro. We show, for the first time, a novel proatherogenic role for both TL1A and DR3 that implicates this pathway as a target for the therapeutic intervention of atherosclerosis.

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Interferon-␥ (IFN-␥) is a pleiotropic cytokine that modulates the immune function, cell proliferation, apoptosis, macrophage activation, and numerous other cellular responses. These biological actions of IFN-␥ are characterized by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanisms through which the cytokine suppresses gene transcription remain largely unclear. We show here for the first time that exposure of macrophages to IFN-␥ leads to a dramatic induction in the expression of the inducible cAMP early repressor (ICER), a potent inhibitor of gene transcription. In addition, a synergistic action of IFN-␥ and calcium in the activation of ICER expression was identified. The IFN-␥-mediated activation of ICER expression was not blocked by H89, bisindoylmaleimide, SB202190, PD98059, W7, and AG490, which inhibit protein kinase A, protein kinase C, p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, calcium-calmodulin-dependent protein kinase, and Janus kinase-2, respectively. In contrast, apigenin, a selective casein kinase 2 (CK2) inhibitor, was found to inhibit response. Consistent with this finding, IFN-␥ stimulated CK2 activity and the level of phosphorylated cAMP response element-binding protein, which is known to induce ICER gene transcription, and this response was inhibited in the presence of apigenin. These studies, therefore, identify a previously uncharacterized pathway, involving the IFN-␥-mediated stimulation of CK2 activity, activation of cAMP response element-binding protein, and increased production of ICER, which may then play an important role in the inhibition of macrophage gene transcription by this cytokine.