KLF4 Modulates Expression of IL-6 in Dendritic Cells via Both Promoter Activation and Epigenetic Modification

Rosenzweig, Jason M.; Glenn, Justin D.; Calabresi, Peter A.; Whartenby, Katharine A.

doi:10.1074/jbc.m113.479576

Cited by 48 publications

(47 citation statements)

References 34 publications

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“…GC treatment is a standard therapy for countering skin inflammation, with GR activation suppressing inflammatory pathways in both keratinocytes and skin immune cells (Pérez, 2011). In immune cells, Klf4 can mediate inflammatory signaling (Chinenov et al, 2014;Feinberg et al, 2007;Rosenzweig et al, 2013), however, whether it does so in keratinocytes was unknown. Taken together, our data show direct cooperation between Klf4 and GR in keratinocyte gene regulation and uncovers a role for Klf4 in regulating anti-inflammatory genes in these cells.…”

Section: Resultsmentioning

confidence: 99%

Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

Sevilla

Latorre

Carceller

et al. 2015

Molecular and Cellular Endocrinology

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The glucocorticoid (GC) receptor (GR) and Kruppel-like factor Klf4 are transcription factors that play major roles in skin homeostasis. However, whether these transcription factors cooperate in binding genomic regulatory regions in epidermal keratinocytes was not known. Here, we show that in dexamethasone-treated keratinocytes GR and Klf4 are recruited to genomic regions containing adjacent GR and KLF binding motifs to control transcription of the anti-inflammatory genes Tsc22d3 and Zfp36. GR- and Klf4 loss of function experiments showed total GR but partial Klf4 requirement for full gene induction in response to dexamethasone. In wild type keratinocytes induced to differentiate, GR and Klf4 protein expression increased concomitant with Tsc22d3 and Zfp36 up-regulation. In contrast, GR-deficient cells failed to differentiate or fully induce Klf4, Tsc22d3 and Zfp36 correlating with increased expression of the epithelium-specific Trp63, a known transcriptional repressor of Klf4. The identified transcriptional cooperation between GR and Klf4 may determine cell-type specific regulation and have implications for developing therapies for skin diseases.

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Section: Resultsmentioning

confidence: 99%

Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

Sevilla

Latorre

Carceller

et al. 2015

Molecular and Cellular Endocrinology

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“…Transcription factors evolved first and the epigenetic modifiers were added later primarily in the metazoan lineage. It is possible that transcription factors indirectly provide the DNA sequence specificity of epigenetic modifiers . A detailed evolutionary analysis will be most useful in bringing out this relationship in the future.…”

Section: Introductionmentioning

confidence: 99%

Gene regulatory networks and epigenetic modifications in cell differentiation

Roy

Kundu

2014

IUBMB Life

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It is becoming increasingly clear that the functionalities of an organism are mostly derived from regulation of its gene repertoire. Specialized cell types are created from pluripotent stem cells by regulating expression of genes. In eukaryotes, genes are primarily regulated by gene regulatory networks consisting of highly sequence-specific transcription factors and epigenetic modifications. The former mode of regulation is more readily reversible and non-heritable across cell generations, whereas the latter mode is less reversible and heritable. In this article, we explore the relationship between cell differentiation and the two modes of regulation of gene expression, focusing primarily on pluripotent and multipotent stem cells. Recent studies suggest that stem cells execute different gene expression programs, probably driven by one or more gene regulatory network(s). It is now also evident that as stem cells differentiate to more specialized progeny cells, rewriting of epigenetic marks occurs in parallel with the change in the pattern of gene expression. A conceptual framework is put forward in which it is proposed that the cell fate determining gene regulatory network in a pluripotent or multipotent cell has the capability to exist in multiple stationary states with each stationary state dictating a particular pattern of gene expression. We also propose that the broad pattern of gene expression in each stationary state, termed the lineage biased state or LIBS, resembles that of a more differentiated progeny cell. The differentiation process leading to a particular progeny cell involves rewriting of epigenetic marks that result in upregulation of genes in a LIBS and silencing of genes involved in alternative LIBS; thus selecting a particular pattern of gene expression and making a lineage commitment. V C 2014 IUBMB Life, 66(2):100-109, 2014

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“…As for proinflammatory cytokine expression, gene transcription not only needs the upregulation of some transcription factors and transcriptional coactivators, but also requires them to bind to the promoters of proinflammatory cytokine genes (24,25). Kruppel-like factor 4 (KLF4), as a transcription factor, can activate target gene promoter via binding to GC-rich or CACCC elements (25) and influence gene transcription (26)(27)(28)(29)(30). In addition, p300/CBP-associated factor (PCAF), as a coactivator, can also regulate the transcription of proinflammatory cytokine gene (31).…”

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confidence: 99%

Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis

Zhang

Xie

et al. 2018

The Journal of Immunology

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Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9–induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9–induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9–mediated IL-23 and IL-36a production of Thy-1N rats.

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KLF4 Modulates Expression of IL-6 in Dendritic Cells via Both Promoter Activation and Epigenetic Modification

Cited by 48 publications

References 34 publications

Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes

Gene regulatory networks and epigenetic modifications in cell differentiation

Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis

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