Abstract
Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. The onset, progression, and resolution of the inflammatory response to endotoxin are usually tightly controlled to avoid chronic inflammation. Members of the NF-κB family of transcription factors are key drivers of inflammation that activate sets of genes in response to inflammatory signals. Such responses are typically short-lived and can be suppressed by proteins that act post-translationally, such as the SOCS (suppressor of cytokine signaling) family. Less is known about direct transcriptional regulation of these responses, however. Here, using a combination of in vitro approaches and in vivo animal models, we show that endotoxin treatment induced expression of the well-characterized transcriptional repressor Krüppel-like factor 3 (KLF3), which, in turn, directly repressed the expression of the NF-κB family member RELA/p65. We also observed that KLF3-deficient mice were hypersensitive to endotoxin and exhibited elevated levels of circulating Ly6C+ monocytes and macrophage-derived inflammatory cytokines. These findings reveal that KLF3 is a fundamental suppressor that operates as a feedback inhibitor of RELA/p65 and may be important in facilitating the resolution of inflammation.
Highlights
Bacterial products such as lipopolysaccharides cause systemic inflammation, resulting in a substantial global health burden
Given early findings that Krüppel-like factor 3 (KLF3) is important for erythroid development, we performed blood counts to determine whether mice lacking KLF3 have altered numbers of circulating hematopoietic cells
This result was confirmed by flow cytometry, in which we observed twice as many circulating CD115ϩ monocytes in Klf3Ϫ/Ϫ mice (Fig. 1C)
Summary
Bacterial products such as lipopolysaccharides (or endotoxin) cause systemic inflammation, resulting in a substantial global health burden. In the absence of KLF3, mice exhibit pronounced systemic inflammation with elevated circulating inflammatory monocytes, constitutive proinflammatory cytokine production, and a heightened response to endotoxin. KLF3 is induced in macrophages following LPS exposure and directly binds and represses the expression of the NF-B subunit gene Rela in a simple feedback inhibition mechanism These findings identify KLF3 as a fundamental suppressor of NF-B– driven inflammation and, importantly, identify a novel repressor of RELA/p65 that acts at the transcriptional level
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