Disease relevance of CEBPB

• These results suggest a new role for Vpr in the pathogenesis of HIV infection, namely, the activation of transcription factors NF-IL-6 and NF-kappaB [1].
• Analysis of cis-acting sites in the CXCL8 promoter revealed that both rhinovirus infection and dsRNA treatment upregulated CXCL8 promoter activation via NF-kappaB and NF-IL6 binding sites [2].
• Activation of the interleukin 6 gene by Mycobacterium tuberculosis or lipopolysaccharide is mediated by nuclear factors NF-IL6 and NF-kappa B [3].
• IL-6 and NF-IL6 in acute-phase response and viral infection [4].
• These data indicate that hypoxia induces expression of IL-6, most likely a result of hypoxic activation at the NF-IL-6 site, and suggest that other genes with regulatory NF-IL-6 sites may also be induced by a similar mechanism [5].

High impact information on CEBPB

• Functional NF-IL6/CCAAT enhancer-binding protein is required for tumor necrosis factor alpha-inducible expression of the granulocyte colony-stimulating factor (CSF), but not the granulocyte/macrophage CSF or interleukin 6 gene in human fibroblasts [6].
• In addition, NF-IL6 is known to form heterodimeric complexes with the NF-kappa B transcription factor, which is also engaged in the transcriptional regulation of these genes [7].
• Functional NF-IL6/CCAAT enhancer-binding protein is required for tumor necrosis factor alpha-inducible expression of the granulocyte colony-stimulating factor (CSF), but not the granulocyte/macrophage CSF or interleukin 6 gene in human fibroblasts [7].
• The indispensable importance of NF-IL6 for regulating gene expression of proinflammatory cytokine genes in response to inflammatory stimuli in vivo remains, however, unclear [7].
• LAP (NF-IL6) transactivates the collagen alpha 1(I) gene from a 5' regulatory region [8].
• CEBPB expression in humans (peripheral blood leukocytes) is found to correlate with muscle strength [9]. Higher expression of CEBPB is hypothesized to reflect a greater proportion of alternatively differentiated macrophages that perform the repair of muscle after injury, based on the cited study in humans and the following evidence from mice [10].

Chemical compound and disease context of CEBPB

• Retinoid antagonism of NF-IL6: insight into the mechanism of antiproliferative effects of retinoids in Kaposi's sarcoma [11].
• Convergent regulation of NF-IL6 and Oct-1 synthesis by interleukin-6 and retinoic acid signaling in embryonal carcinoma cells [12].

Biological context of CEBPB

• Within this DNA fragment, there were two novel 9-bp motifs (-90/-82 and -40/-32) with high homology to the nuclear factor-IL6 (NF-IL6) binding site [13].
• These data demonstrate that RelA and members of the C/EBP/NF-IL-6 family can functionally cooperate in transcriptional activation of the IL-8 gene and suggest a common mechanism for inducible regulation of cytokine gene expression [14].
• Mutational analyses of RelA demonstrate that the C-terminal transactivation domain and the DNA binding domain are required for synergistic activation with NF-IL-6 [14].
• Our studies show that HSF1 represses the lipopolyliposaccharide-induced transcription of the IL-1beta promoter through direct interaction with the nuclear factor of interleukin 6 (NF-IL6, also known as CCAAT enhancer binding protein (C/EBPbeta), an essential regulator in IL-1beta transcription [15].
• Exploring transcription factor binding properties of several non-coding DNA sequence elements in the human NF-IL6 gene [16].

Anatomical context of CEBPB

• Maximal transcriptional activation by PMA in Jurkat T lymphocytes was shown to require intact binding sites for both NF-kappa B and NF-IL-6 [14].
• The results of the present study indicate that NF-IL-6 interacts with NF-kappaB in regulating the expression of IL-8 in cultured human airway epithelial cells exposed to LOP, the biological products of ozone in the lung [17].
• Transcriptional regulation of cyclooxygenase-2 in the human microvascular endothelial cell line, HMEC-1: control by the combinatorial actions of AP2, NF-IL-6 and CRE elements [18].
• Each site is functionally important and contributes independently to transcription of the NF-IL6 gene in U937 cells [19].
• NF-IL6 is an important transcriptional regulator of genes induced in activated monocytes/macrophages, and NF-IL6 is the only CCAAT/enhancer-binding protein (C/EBP) family member whose steady-state mRNA levels increase upon activation of monocytes (1) [19].

Associations of CEBPB with chemical compounds

• We have previously reported in human normal TEC that clustering of the laminin receptor alpha6beta4 integrin induced by thymocyte contact or monoclonal antibody-mediated cross-linking regulates IL-6 gene expression via activation of NF-kappaB and NF-IL6 transactivators [20].
• The anti-inflammatory glucocorticoid dexamethasone inhibited NF-kappaB translocation and the promoter binding of NF-kappaB, AP-1, and NF-IL-6 [21].
• Furthermore, exogenous prostaglandin E2 stimulated AP-1 and NF-IL-6 binding to the IL-8 promoter [21].
• Cockroach extract-induced regulation of NF-IL6 was due to active serine proteases in the extract as well as activation of protease activated receptor (PAR)-2, but not PAR-1 [22].
• Taken together, the results suggest that asbestos-induced redox changes and phosphorylation events, mediated by staurosporine-sensitive and tyrosine kinase(s), activate nuclear proteins which recognize the NF-kappaB/NF-IL-6 binding sites of the IL-8 promoter and contribute to the regulation of IL-8 gene expression [23].

Physical interactions of CEBPB

• We show for the first time that HSF1 binds directly to NF-IL6 in vivo and antagonizes its activity [15].
• In this regard, it is noteworthy that both an NF-IL6 binding site and an NFkB binding site are present in the inducible genes such as IL-6, IL-8, and several acute-phase genes [4].
• Mutation of either the AP-1 or NF-IL6 binding site did not abolish IL-8 gene repression by dexamethasone, suggesting that these sites were not targets for dexamethasone [24].
• In addition, HSF2 is not capable of binding to NF-IL6 [25].
• Based on the results obtained from the present study, we conclude that the IL1B promoter is a Tax-responsive sequence as a result of ability of Tax to induce binding of NF-IL6 and Spi-1 to the IL1B promoter sequence through protein-protein interaction [26].

Regulatory relationships of CEBPB

• Recombinant NF-IL6 activated the human IL-6 promoter in a sequence-specific manner [27].
• DNA mobility shift assay revealed specific binding of nuclear protein(s) from LAM-, LPS-, or TNF-alpha-stimulated THP-1 cells to the NF-IL6 motifs [13].
• HSF1 has little effect on IL-1beta promoter activity stimulated by the essential monocytic transcription factor Spi.1 but is strongly inhibitory to transcriptional activation by NF-IL6 and to the synergistic activation by NF-IL6 and Spi [15].
• Activation of transcription factors NF-kappaB and NF-IL-6 by human immunodeficiency virus type 1 protein R (Vpr) induces interleukin-8 expression [1].
• Both IL-1 and IL-4 stimulated NF-IL6 activity as early as 30 minutes after treatment [28].

Other interactions of CEBPB

• Site-directed mutagenesis demonstrated that the two NF-IL-6 motifs could be independently activated by LAM, LPS, or TNF-alpha and that they acted in an orientation-independent manner [13].
• Transient cotransfection analyses indicate that the cooperative association of NF-IL-6 and RelA with the IL-8 promoter results in synergistic transcriptional activation [14].
• Furthermore, transfected NF-IL6 synergized strongly with co-transfected NF-kappa B, particularly with RelA (p65) [29].
• However, IL-4 does not globally suppress the activity of all DNA-binding proteins because IL-4 treatment did not reduce the levels of NF-IL-6 or NF-IL-1 beta B in the same cells [30].
• Gel-shift analysis confirmed the up-regulation of AP-1 and CRE nuclear binding proteins, though there was little or no OKA-induced nuclear protein binding to SP-1, AP-2, NF-kappaB or NF-IL-6 regulatory elements [31].

Analytical, diagnostic and therapeutic context of CEBPB

• Furthermore, CEBPB has been mapped to 20q13.1 by fluorescence in situ hybridization [32].
• Southern blot analysis demonstrated the high-degree conservation of the NF-IL6 gene through evolution and the existence of several other related genes sharing the DNA-binding domain [27].
• NF-IL6 protein, however, was detected in nuclear extracts of these cells by Western blotting [33].
• The nuclear factor interleukin-6 (NF-IL6) and signal transducer and activator of transcription-3 (STAT-3) signalling pathways co-operate to mediate the activation of the hsp90beta gene by interleukin-6 but have opposite effects on its inducibility by heat shock [34].
• A high-resolution radiation hybrid map encompassing 9.5 Mb between the PLC and the CEBPB genes was constructed using 68 markers: 25 polymorphic markers, 15 known genes, 21 ESTs, and 7 random genomic sequences [35].

References