Glucocorticoid and cytokine crosstalk: Feedback, feedforward, and co-regulatory interactions determine repression or resistance

Robert Newton, Suharsh Shah, Mohammed O Altonsy, Antony N Gerber, Robert Newton, Suharsh Shah, Mohammed O Altonsy, Antony N Gerber

Abstract

Inflammatory signals induce feedback and feedforward systems that provide temporal control. Although glucocorticoids can repress inflammatory gene expression, glucocorticoid receptor recruitment increases expression of negative feedback and feedforward regulators, including the phosphatase, DUSP1, the ubiquitin-modifying enzyme, TNFAIP3, or the mRNA-destabilizing protein, ZFP36. Moreover, glucocorticoid receptor cooperativity with factors, including nuclear factor-κB (NF-κB), may enhance regulator expression to promote repression. Conversely, MAPKs, which are inhibited by glucocorticoids, provide feedforward control to limit expression of the transcription factor IRF1, and the chemokine, CXCL10. We propose that modulation of feedback and feedforward control can determine repression or resistance of inflammatory gene expression toglucocorticoid.

Keywords: gene expression; gene regulation; glucocorticoid; glucocorticoid receptor; inflammation.

Conflict of interest statement

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Figures

Figure 1.
Figure 1.
Differential effects of dexamethasone on IL1B-induced mRNAs. Data are derived from King et al. (11) where full details can be found. A, expression of 39 of the most highly IL1B-induced mRNAs in A549 cells was examined by qPCR following no treatment (NT) or treatment with dexamethasone (1 μm) (Dex), IL1B (1 ng/ml), or IL1B + Dex for 6 h. Data for each mRNA were normalized to GAPDH and are expressed as a percentage of IL1B treated, which is set to 100% (blue), and are presented as a heat map (white = 0%). IL1B-induced mRNAs are ranked according to the effect of dexamethasone with IL6 being the most repressed and CSF3 (G-CSF) being enhanced. The effects of NF-κB inhibition, using adenoviral overexpression of the dominant inhibitor, IκBαΔN, or a control virus (Control), are also expressed as a percentage of IL1B-treated and are shown as a heat map. B, A549 cells were stimulated with IL1B (1 ng/ml) in the absence or presence of the indicated concentrations of dexamethasone prior to harvesting at 6 h for qPCR analysis of the 39 mRNAs in A. Data (n = 6) for each mRNA (indicated by an x) were plotted as a percentage of IL1B treatment. The most potently repressed mRNA (IL1B) along with mRNAs showing intermediate (IFIT3 isoform 2, EFNA1, CFB) and no (IL32) repression or enhancement (CSF3) by dexamethasone are shown (upper panel). The maximal effect (Max. effect) of dexamethasone (i.e. at 1 μm) and the EC50 were calculated for each mRNA that showed significant repression. These are plotted (lower panel) to show the correlation between potency and repression by dexamethasone. Error bars indicate ± S.E.
Figure 2.
Figure 2.
Regulatory loops controlling inflammatory gene expression.A, schematic showing activation of MAPK pathways and NF-κB by IL1B or TNF leading to the expression of inflammatory genes. MAPKs induce the expression of the phosphatase, DUSP1, which provides feedback control to switch off MAPK activity. NF-κB binds κB sites in promoters of target genes. This activates transcription of NFKBIA, TNFAIP3, and IRAK3 to increase their expression and leads to feedback inhibition of NF-κB or IL1B/TNF signaling. Expression of DUSP1, NFKBIA, TNFAIP3, and IRAK3 can also be enhanced by glucocorticoids (GC). B, type I coherent and incoherent feedforward loops are depicted. In the type I coherent feedforward loop (panel i), X positively regulates Y, and Z is positively regulated by both X and Y. In the type I incoherent feedforward loop (panel ii), X positively regulates both Y and Z, but Y negatively regulates Z. C, schematic showing how feedback and feedforward regulation may interplay to regulate AU-rich element (ARE)-containing inflammatory mRNAs. Panel i, pro-inflammatory stimuli, here IL1B, activate MAPK pathways, leading to the expression of ARE-containing mRNAs, such as TNF. MAPK activation not only also induces expression of the feedback regulator, DUSP1, but also promotes expression of ZFP36. ZFP36 is a feedforward regulator that leads to mRNA destabilization of ARE-containing mRNAs, such as TNF. Thus, the MAPK-dependent induction of ZFP36 leads to repression of ARE-containing mRNAs and constitutes a classic type I incoherent feedforward loop. Note that expression of ARE-containing mRNAs and ZFP36 is also likely to involve NF-κB, and this is not depicted. Panel ii, Following loss, or silencing, of DUSP1, MAPK activity is enhanced and leads to increased expression of downstream genes. However, expression of ZFP36 is also enhanced, and this acts to reduce expression of ARE-containing mRNAs, such as TNF. Panel iii, ZFP36 expression is up-regulated by glucocorticoids alone, but ZFP36 expression induced by the inflammatory stimulus is reduced by glucocorticoid, in part due to reduced MAPK activity following the induction of DUSP1. Although these effects may combine to promote expression of the hypo-phosphorylated and more active, mRNA-destabilizing form of ZFP36, silencing of both DUSP1 and ZFP36 showed little effect on the repression of TNF by glucocorticoid. Additional, glucocorticoid-induced effector processes are therefore likely to play additional repressive roles.
Figure 3.
Figure 3.
GR and NF-κB (RELA) recruitment to inflammatory gene loci. Data from a ChIP-seq analysis by Kadiyala et al. (15) are shown. BEAS-2B cells were treated for 1 h with Dex (1 μm), TNF (20 ng/ml), or Dex plus TNF for 1 h prior to ChIP-seq analysis. Occupancy of GR and RELA at genomic loci in the vicinity of six genes is shown. A, inflammatory feedback control genes, where GR and RELA may cooperate to enhance or maintain the expression of TNFAIP3 (panel i); NFKBIA (panel ii); and IRAK3 (panel iii). In each case, GR and RELA are recruited to the gene loci following dexamethasone or TNF treatment, respectively. In the context of dexamethasone plus TNF, both GR and RELA are both recruited to at least one DNA region in common (red arrow). Although overall GR occupancy at each gene locus was largely unaffected by TNF, site-specific differences are apparent. Conversely, co-treatment differentially affected RELA occupancy, which was increased at an intronic region for TNFAIP3, slightly decreased on NFKBIA, and markedly increased at the IRAK3 promoter. B, GR and RELA co-recruitment to the SOD2 (panel i), ZCH12A (panel ii), and IL32 (panel iii) gene loci. SOD2 and IL32 are induced by inflammatory stimuli, and here TNF induces RELA binding to each gene locus. In the additional presence of dexamethasone, RELA binding is slightly reduced (red arrow). However, although GR occupancy at this same region was not readily apparent with dexamethasone alone, with TNF plus dexamethasone, GR recruitment is induced (red arrow). GR occupancy at regions that either did not show GR binding, or only showed weak GR binding, in the presence of dexamethasone alone were also enhanced for both SOD2 and IL32 with dexamethasone plus TNF (black arrows). These regions did not show material RELA occupancy. With ZC3H12A, RELA occupancy was induced to multiple intronic regions by TNF. Although dexamethasone reduced RELA occupancy, GR was recruited to these same regions with TNF plus dexamethasone (red arrows). Binding of RELA and GR at a 5′ region was markedly enhanced by TNF plus dexamethasone (black arrows), whereas neither TNF nor dexamethasone alone showed any marked effect on occupancy.
Figure 4.
Figure 4.
Loss of feedforward control may promote glucocorticoid resistance.A, schematic showing the regulation of IRF1, as well as IRF1-dependent gene expression. Pro-inflammatory stimuli (IL1B) induce NF-κB activity, leading to the transcriptional activation of IRF1. IRF1 expression is rapidly induced to promote expression of downstream IRF1-dependent genes. Many IRF1-depedent genes, for example CXCL10, are also directly regulated by NF-κB to constitute a type I coherent feedforward loop. Pro-inflammatory stimuli, such as IL1B, promote activation of MAPK pathways. Acting via multiple mechanisms, MAPKs promote the switching off and/or loss of IRF1 expression. This terminates IRF1 expression and prevents continued expression of IRF1-dependent genes. In the presence of glucocorticoid (GC), DUSP1 expression is enhanced. By reducing MAPK activity, glucocorticoids reduce incoherent feedforward control of IRF1, and this promotes IRF1 expression. This effect also occurs following MAPK inhibition. Maintenance of IRF1 expression helps CXCL10 to escape the otherwise repressive effects of the glucocorticoid. However, many other IRF1-dependent genes (for examples, see CMPK2, MX1, IFIT1, and others on Fig. 1A) show significant repression by glucocorticoids. Therefore, the existence of additional mechanisms of repression must be invoked. B, data are modified from Shah et al. (77) where full details can be found. A549 cells were either not treated, or treated with IL1B (1 ng/ml), for the times indicated prior to Western blotting and qPCR analysis of IRF1 and GAPDH (upper and middle panels) or qPCR of established IRF1-dependent genes. Spike kinetics for IFR1 mRNA and protein, as well as late-phase kinetics for IRF1-dependent genes, is shown.

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