Disease relevance of Irf2

• ICSBP-/- and to a lesser degree also IRF2-/- mice were highly susceptible to Listeria infection [1].
• IRF-2-deficient mice exhibited bone marrow suppression of hematopoiesis and B lymphopoiesis and mortality following lymphocytic choriomeningitis virus infection [2].
• We have used experimental leishmaniasis to show that, like IRF-1(-/)- mice, IRF-2(-/)- mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation [3].
• Brucella abortus S2308-infected IRF-1-/- mice were dead within 2 wk postinfection, while IRF-2-/- mice contained less splenic Brucella CFU than wild-type mice at the early stage of infection [4].
• A peptide fragment of approximately 14 K, IRF-2(113), which corresponds to the N-terminal 113 amino acids of the intact IRF-2 protein, has been expressed in a functional form in Escherichia coli [5].

High impact information on Irf2

• The transcriptional activator interferon regulatory factor 1 (IRF-1) and its antagonistic repressor IRF-2 are regulators of the interferon (IFN) system and of cell growth [6].
• In contrast, IRF-2-deficient fibroblasts showed up-regulated type I IFN induction by NDV infection [2].
• CD8(+) T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-alpha/beta signaling [7].
• IRF-2 may represent a unique negative regulator, attenuating IFN-alpha/beta-induced gene transcription, which is necessary for balancing the beneficial and harmful effects of IFN-alpha/beta signaling in the immune system [7].
• We show that the IRF-2 oncoprotein represses virus-induced IFN-beta gene transcription via a novel mechanism [8].

Biological context of Irf2

• Furthermore, we observed using reverse transcription-polymerase chain reaction that the IRF-1 mRNA expression was more abundant in confluent cells than growing cells, whereas IRF-2 expression did not change with R3T3 cell growth [9].
• TPA treatment leads to recruitment of IRF-2 to 32kb-150 of the endogenous NMHC-A gene and acetylation of the core histones surrounding this region [10].
• IRF-2 is involved in up-regulation of nonmuscle myosin heavy chain II-A gene expression during phorbol ester-induced promyelocytic HL-60 differentiation [10].
• IRF-2, which is known to either repress or activate target gene expression, acts as a transcriptional activator in the context of the 32kb-150 reporter gene [10].
• Together, these results indicate that IRF-2 contributes to transcriptional activation of the NMHC-A gene via 32kb-150 during TPA-induced differentiation of HL-60 cells [10].

Anatomical context of Irf2

• Furthermore, after treatment of promyelocytic HL-60 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), which triggers differentiation into macrophages, both NMHC-A expression and IRF-2 expression were found to be up-regulated with a similar time course [10].
• We further show that in the developing mouse lens, IRF-1 and IRF-2 are expressed at high levels in differentiated lens fiber cells with very low and barely detectable levels in undifferentiated lens epithelial cells [11].
• Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development [2].
• We have generated mice deficient in either IRF-1 or IRF-2 by gene targeting in embryonic stem cells [2].
• NK (but not NK(+) T) cell numbers are decreased in IRF-2(-/)- mice, and the NK cells that are present are immature in phenotype [3].

Associations of Irf2 with chemical compounds

• In response to 35 mg/kg LPS, IRF-1-, but not IRF-2-deficient mice, exhibited much poorer induction of COX-2 gene expression in both the livers and lungs [12].
• IRF-2 antisense oligonucleotide pretreatment did not affect the onset of apoptosis after serum removal; instead, it increased AT2 receptor binding and enhanced angiotensin II-mediated apoptosis [13].
• Both the F2 and F0 cell lines were synchronized in the G1 phase by isoleucine deprivation, and IRF-2 was induced by DOX on release of cells from the cell cycle block [14].
• IRF-2-/- M phi produced less LPS-induced NO2- than IRF-2+/- or C57BL/6 M phi [15].
• In this study we identified, by mass spectrometry, two lysine residues in the DNA binding domain (DBD), Lys-75 and Lys-78, to be the major acetylation sites in IRF-2 [16].

Physical interactions of Irf2

• Chromatin immunoprecipitation assays showed that IRF-2 interacted with p300 and bound to the endogenous H4 promoter only in growing cells, although the levels of total IRF-2 were comparable in both growing and growth-arrested cells [16].
• IRF-1 functions as an activator whereas IRF-2 binds to the same cis-elements and can repress IRF-1 action [17].

Regulatory relationships of Irf2

• The kappa intron ISRE specifically bound IFN response factor-1 (IRF-1) and the constitutively expressed IRF-2 [18].
• Interferon regulatory factor-2 is a transcriptional activator in muscle where It regulates expression of vascular cell adhesion molecule-1 [19].

Other interactions of Irf2

• We conclude that, in confluent cells, the enhanced expression of IRF-1 antagonizes the IRF-2 effect and increases the AT2 receptor expression [9].
• Induction of IL-12 p40 mRNA by LPS was markedly diminished in both IRF-1(-/-) and IRF-2(-/-) macrophages [20].
• Impaired class II transactivator expression in mice lacking interferon regulatory factor-2 [21].
• IL-12R beta 2 mRNA levels from LPS-challenged IRF-2(-/-) mice were significantly different after 1, 6, and 8 h, suggesting that both diminished IL-12 and altered IL-12R expression contribute to the paucity of IFN-gamma produced [22].
• IRF-2(-/-) mice were also more refractory to TNF-alpha challenge than were control mice, which was consistent with their diminished sensitivity to LPS, yet no significant difference in the mRNA expression of TNFRs was observed [22].

Analytical, diagnostic and therapeutic context of Irf2

• Consistent with this result, gel mobility shift assay demonstrated that growing R3T3 cells exhibited only IRF-2 binding, whereas confluent cells exhibited both IRF-1 and IRF-2 binding [9].
• IRF-1 and IRF-2 were confirmed to activate and repress expression of the COX-2 promoter, respectively, in a transient transfection system and the role of specific DNA binding sites confirmed by site-specific mutagenesis [12].
• Here we show that naive mice lacking the transcription factor, interferon regulatory factor 2 (IRF-2), exhibited signal transducer and activator of transcription 6 (Stat6)-independent expansion of basophils in the periphery [23].
• In addition, northern blot analysis showed that the IRF-2 gene expression in clone Kb-S27 was upregulated when compared with the other IFN-inducible clones [24].

References