Interferon-γ Stimulates the Expression of the Inducible cAMP Early Repressor in Macrophages through the Activation of Casein Kinase 2

Abstract

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.

Effects of Forskolin on Kupffer Cell Production of Interleukin-10 and Tumor Necrosis Factor Alpha Differ from Those of Endogenous Adenylyl Cyclase Activators: Possible Role for Adenylyl Cyclase 9

“…We could not find that cAMP-elevating agents were effective in inducing IL-10 transcription in Kupffer cells, and we observed only a nonsignificant tendency of enhanced IL-10 levels by PGE 2 . Several isoforms of CREB and C/EBP with different abilities to confer cAMP-mediated gene transcription are expressed in macrophages, and even inhibitory isoforms like inducible cAMP early repressor and C/EBP liver-enriched inhibitory protein exist (2,13,21). The relative expression of inhibitory and activating factors has not been studied in Kupffer cells but may explain that the potential of cAMP to induce IL-10 differs from that of other macrophage populations.…”

Adenine Nucleotides Inhibit Cytokine Generation by Human Mast Cells through a Gs-Coupled Receptor

“…5) thus suggest a component of ICER induction that is H89 resistant and that may recapitulate inhibitory pathways initiated by other G s -coupled receptors. This component may reflect the capacity of such receptor systems to activate kinases other than PKA that can target CREB in immune cells (65). Based on our previous studies (37), the particular sensitivity of cys-LT-mediated cytokine generation to inhibition by nucleotides may reflect an absolute requirement for NF-AT, a target of ICER.…”

Phosphorylation of RIG-I by Casein Kinase II Inhibits Its Antiviral Response

“…It usually presents as a tetrameric holoenzyme complex of two catalytic subunits (alpha and/or alphaЈ) and two regulatory beta subunits, phosphorylates more than 300 substrates, and controls a wide range of processes, including the regulation of the cell cycle, apoptosis, transformation, and circadian rhythm (20). Recent evidences suggest a potentially important role for CK2 in the control of the inflammatory response (11,13). However, whether CK2 is involved in viral infections has not been studied.…”