Abstract
BackgroundInflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood.ResultsWe investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers.ConclusionsPro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-656) contains supplementary material, which is available to authorized users.
Highlights
Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes
GR regulates transcription by either binding directly to specific DNA sequences known as glucocorticoid response elements (GREs) or by tethering to other DNA-bound regulators, such as Activator Protein (AP)1, Nuclear Factor (NF) κB and Signal Transducers and Activators of Transcription (STAT) family members [3]
We further evaluated the significance of differences in gene expression within clusters by the Mann– Whitney test and validated the results for a limited number of genes by RT-Quantitative PCR (qPCR)
Summary
Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. Preserving homeostasis is the primary function of the innate immune system that detects “danger and stranger” signals and eliminates invading microorganisms, responds to irritation and injury and eventually initiates tissue repair. Innate immune cells, such as macrophages, glands, which attenuate the expression of inflammatory cytokines [1]. These potent anti-inflammatory properties made glucocorticoids exceedingly common for managing a wide range of autoimmune and inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, psoriasis and multiple sclerosis [2]. Prolonged glucocorticoid treatment induces cells polarization toward a new phenotype with either pro- or anti-inflammatory properties [5,6]
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