Krüppel-Like Factor 5 Protects against Murine Colitis and Activates JAK-STAT Signaling In Vivo

Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2012; 7(5):e38338. DOI: 10.1371/journal.pone.0038338
Source: PubMed


Inflammatory bowel disease (IBD), which is characterized by chronic or recurring inflammation of the gastrointestinal tract, affects 1.4 million persons in the United States alone. KLF5, a Krüppel-like factor (KLF) family member, is expressed within the epithelia of the gastrointestinal tract and has been implicated in rapid cell proliferation, migration, and remodeling in a number of tissues. Given these functions, we hypothesized that constitutive Klf5 expression would protect against the development of colitis in vivo. To examine the role of KLF5 in vivo, we used the Villin promoter to target Klf5 to the entire horizontal axis of the small intestine and colon. Villin-Klf5 transgenic mice were born at normal Mendelian ratios and appeared grossly normal to at least 1 year of age. Surprisingly, there were no significant changes in cell proliferation or in the differentiation of any of the intestinal lineages within the duodenum, jejunum, ileum, and colon of Villin-Klf5 mice, compared to littermate controls. However, when Villin-Klf5 mice were treated with dextran sodium sulfate (DSS) to induce colitis, they developed less colonic injury and significantly reduced disease activity scores than littermate controls. The mechanism for this decreased injury may come via JAK-STAT signaling, the activation of which was increased in colonic mucosa of DSS treated Villin-Klf5 mice compared to controls. Thus, KLF5 and its downstream mediators may provide therapeutic targets and disease markers for IBD or other diseases characterized by injury and disruption of intestinal epithelia.

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Available from: Marie-Pier Tetreault, Aug 13, 2014
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    • "As the glucocorticoid receptor can mediate the effects of progestin on uterine inflammatory response (Guo et al. 2012, Lei et al. 2012), The interaction of KLF with progesterone-dependent transcriptional circuitry is a possible node by which KLFs may exert their control over inflammatory events in the uterus. Additional pathways that have been linked to KLFs and that may underlie a number of uterine pathologies when these KLFs are aberrantly expressed include: the promotion by KLF17 of epithelial-to-mesenchymal transitions through induction of TWIST1 in endometrial cancer (Dong et al. 2014); the coactivation by KLF6 of NFkB signaling via its induction of the cytokines tumor necrosis factor a and interleukin 6 (Zhang et al. 2014b) in the pathogenesis of endometriosis; KLF5-mediated activation of the JAK–STAT signaling pathway (Tetreault et al. 2012), the latter being a key mediator of leukemia inhibitory factor that controls embryo implantation and hence successful pregnancy (Rosario et al. 2014); and KLF14-(de Assuncao et al. 2014) and KLF11-(Zheng et al. 2014) mediated activation of lipid and metabolic signaling, respectively, processes that when dysregulated can lead to abnormal metabolism and increased risk of endometrial cancer. "
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    ABSTRACT: Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.
    Journal of Molecular Endocrinology 02/2015; 54(2). DOI:10.1530/JME-14-0310 · 3.08 Impact Factor
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    • "KLF5 regulates proliferation, differentiation, and apoptosis, and its expression is upregulated during development and in certain disease states, such as cancer [6], [7], [8], [9]. In intestinal cells, KLF5 promotes tumor progression [10], [11], [12] and mediates intestinal epithelial cell hyperproliferation and regenerative responses in response to infection and chronic inflammation [13], [14], [15]. "
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    ABSTRACT: Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. H. pylori expresses a repertoire of virulence factors that increase gastric cancer risk, including the cag pathogenicity island and the vacuolating cytotoxin (VacA). One host element that promotes carcinogenesis within the gastrointestinal tract is Krüppel-like factor 5 (KLF5), a transcription factor that mediates key cellular functions. To define the role of KLF5 within the context of H. pylori-induced inflammation and injury, human gastric epithelial cells were co-cultured with the wild-type cag+ H. pylori strain 60190. KLF5 expression was significantly upregulated following co-culture with H. pylori, but increased expression was independent of the cag island or VacA. To translate these findings into an in vivo model, C57BL/6 mice were challenged with the wild-type rodent-adapted cag+ H. pylori strain PMSS1 or a PMSS1 cagE− isogenic mutant. Similar to findings in vitro, KLF5 staining was significantly enhanced in gastric epithelium of H. pylori-infected compared to uninfected mice and this was independent of the cag island. Flow cytometry revealed that the majority of KLF5+ cells also stained positively for the stem cell marker, Lrig1, and KLF5+/Lrig1+ cells were significantly increased in H. pylori-infected versus uninfected tissue. To extend these results into the natural niche of this pathogen, levels of KLF5 expression were assessed in human gastric biopsies isolated from patients with or without premalignant lesions. Levels of KLF5 expression increased in parallel with advancing stages of neoplastic progression, being significantly elevated in gastritis, intestinal metaplasia, and dysplasia compared to normal gastric tissue. These results indicate that H. pylori induces expression of KLF5 in gastric epithelial cells in vitro and in vivo, and that the degree of KLF5 expression parallels the severity of premalignant lesions in human gastric carcinogenesis.
    PLoS ONE 01/2013; 8(1):e54344. DOI:10.1371/journal.pone.0054344 · 3.23 Impact Factor
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    ABSTRACT: The mechanisms by which cells control their growth and behavioral identities are complex and require adaptability to environmental changes. Transcription factors act as master controllers of many of these pivotal points through their ability to influence the expression of many thousands of downstream genes, and increasingly research is showing that transcription factor regulation of target genes can change in response to environmental stimuli and cell type such that their function is not prescribed but rather context-dependent. Krüppel like factor 5 (KLF5) is an example of such a transcription factor, where evidence of disparate effects on cell growth and differentiation in normal and transformed tissue are clear. Here we present and discuss the literature covering the differential roles of KLF5 in particular tissues and cancer states, and the mechanisms by which these differences are effected through the regulation of KLF5 protein function in response to different cellular states and the direct effect on target gene expression. © 2013 IUBMB Life, 2013.
    International Union of Biochemistry and Molecular Biology Life 12/2013; 65(12). DOI:10.1002/iub.1233 · 3.14 Impact Factor
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