Dataset Information

CCAAT/enhancer-binding protein ? and NF-?B mediate high level expression of chemokine genes CCL3 and CCL4 by human chondrocytes in response to IL-1?.

ABSTRACT: A large set of chemokines is highly up-regulated in human chondrocytes in response to IL-1? (Sandell, L. J., Xing, X., Franz, C., Davies, S., Chang, L. W., and Patra, D. (2008) Osteoarthr. Cartil. 16, 1560-1571). To investigate the mechanism of transcriptional regulation, deletion constructs of selected chemokine gene promoters, the human CCL3 (MIP-1?) and CCL4 (MIP-1?), were transfected into human chondrocytes with or without IL-1?. The results show that an IL-1?-responsive element is located between bp -300 and -140 of the CCL3 promoter and between bp -222 and -100 of the CCL4 promoter. Because both of these elements contain CCAAT/enhancer-binding protein ? (C/EBP?) motifs, the function of C/EBP? was examined. IL-1? stimulated the expression of C/EBP?, and the direct binding of C/EBP? to the C/EBP? motif was confirmed by EMSA and ChIP analyses. The -300 bp CCL3 promoter and -222 bp CCL4 promoter were strongly up-regulated by co-transfection with the C/EBP? expression vector. Mutation of the C/EBP? motif and reduction of C/EBP? expression by siRNA decreased the up-regulation. Additionally, another cytokine-related transcription factor, NF-?B, was also shown to be involved in the up-regulation of chemokines in response to IL-1?, and the binding site was identified. The regulation of C/EBP? and NF-?B was confirmed by the inhibition by C/EBP? and NF-?B and by transfection with C/EBP? and NF-?B expression vectors in the presence or absence of IL-1?. Taken together, our results suggest that C/EBP? and NF-?B are both involved in the IL-1?-responsive up-regulation of chemokine genes in human chondrocytes. Time course experiments indicated that C/EBP? gradually and steadily induces chemokine up-regulation, whereas NF-?B activity was highest at the early stage of chemokine up-regulation.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC2963416 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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CCAAT/enhancer-binding protein β and NF-κB mediate high level expression of chemokine genes CCL3 and CCL4 by human chondrocytes in response to IL-1β.

Zhang Zhiqi Z Bryan Jennifer L JL DeLassus Elizabeth E Chang Li-Wei LW Liao Weiming W Sandell Linda J LJ

The Journal of biological chemistry 20100811 43

A large set of chemokines is highly up-regulated in human chondrocytes in response to IL-1β (Sandell, L. J., Xing, X., Franz, C., Davies, S., Chang, L. W., and Patra, D. (2008) Osteoarthr. Cartil. 16, 1560-1571). To investigate the mechanism of transcriptional regulation, deletion constructs of selected chemokine gene promoters, the human CCL3 (MIP-1α) and CCL4 (MIP-1β), were transfected into human chondrocytes with or without IL-1β. The results show that an IL-1β-responsive element is located b ...[more]

PMID: 20702408

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Project description:CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.

Dataset Information

CCAAT/enhancer-binding protein ? and NF-?B mediate high level expression of chemokine genes CCL3 and CCL4 by human chondrocytes in response to IL-1?.

Publications

CCAAT/enhancer-binding protein β and NF-κB mediate high level expression of chemokine genes CCL3 and CCL4 by human chondrocytes in response to IL-1β.

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