Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
Volume 1779, Issue 6-7, Pages 383-389Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbagrm.2008.04.006
Keywords
acute phase protein; proinflammatory cytokine; inflammatory transcriptome; functional gene cluster analysis; transcription factor binding site
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The transcriptome profile of human monocyte-clerived macrophages stimulated in vitro by low doses of IL-1 or IL-6 was analyzed by microarrays (Affymetrix, HG-U133A) in 5 independent experiments. Out of 4886 probe sets consistently detected in all 5 array replicates we found approximately 300 genes (FDR < 5%) modulated by IL-1 and/or IL-6, among which 34 may be regarded as novel cytokine-responsive macrophage genes of various function. Detailed analysis indicates that cytokine-responsive genes include 125 transcripts significantly up-regulated by IL-I and only 39 transcripts up-regulated by IL-6, whereas the number of downregulated transcripts is lower and almost equal for both cytokines. These data indicate that, in comparison to liver cells, IL-1 is more potent than IL-6 in modulating gene expression of human macrophages. Hierarchical clustering analysis of these transcripts yielded 7 separate gene clusters. The most abundant group contains genes strongly activated by IL-1 alone and coding for chemokines, cytokines and their receptors, the components of intracellular signaling as well as transcription factors from NF-kB family. In order to validate the results obtained by microarray analysis the expression of 5 genes from various clusters was determined by quantitative RT-PCR. Moreover, the putative promoter regions of all cytokine-responsive genes were subjected to the in silico identification of transcription factor binding sites (TFBS). We found that TFBS corresponding to ReIA/NF-kB is the most strongly over-re presented group and we demonstrated involvement of NF-kB in the expression of selected genes. (c) 2008 Elsevier B.V. All rights reserved.
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