Klf10 deficiency in mice exacerbates pulmonary inflammation by increasing expression of the proinflammatory molecule NPRA.

KLF10 is a transforming growth factor (TGF)-ß/Smad downstream regulated gene. KLF10 binds to the promoter of target genes and mimics the effects of TGF-ß as a transcriptional factor. In our laboratory, we noted that Klf10 deficiency in mice is associated with significant inflammation of the lungs. However, the precise mechanism of this association remains unknown. We previously identified NPRA as a target gene potentially regulated by KLF10 through direct binding; NPRA knockout have known that prevented lung inflammation in a mouse model of allergic asthma. Here, we further explored the regulatory association between KLF10 and NPRA on the basis of the aforementioned findings. Our results demonstrated that KLF10 acts as a transcriptional repressor of NPRA and that KLF10 binding reduces NPRA expression in vitro. Compared with wild-type mice, Klf10-deficient mice were more sensitive to lipopolysaccharide or ovalbumin challenge and showed more severe inflammatory histological changes in the lungs. Moreover, Klf10-deficient mice showed pulmonary neutrophil accumulation. These findings collectively reveal the precise site where KLF10 signaling affects pulmonary inflammation by attenuating NPRA expression. They also verify the importance of KLF10 and atrial natriuretic peptide/NPRA in exerting influences on chronic pulmonary disease pathogenesis.

KLF10 affects pancreatic function via the SEI-1/p21Cip1 pathway.

TGF-ß plays a significant role in regulating pancreas islet function and maintaining their mass. KLF10, a TGF-ß downstream gene, belongs to a group of Krüppel-like transcription factors that bind to the promoters of target genes and produce effects that mimic TGF-ß as a tumor suppressor. Using ChIP-chip screening, SEI-1 was identified as a target gene that may be regulated by KLF10. We conducted a series of assays to verify the presence of unknown regulation events between SEI-1 and KLF10. These showed that KLF10 transcriptionally activates the SEI-1 promoter and, furthermore, induces SEI-1 protein expression in pancreatic carcinoma cells. SEI-1 is one of the key factors involved in cell cycle control through the regulation of other transcription factors such as the p21(Cip1) gene. Interestingly, it has been shown previously that p21(Cip1) is indirectly activated by KLF10. Our results first demonstrated that KLF10 acts as a transcriptional activator on SEI-1, which can then result in increased p21(Cip1) expression. Furthermore, KLF10-deficiency in mice is associated with a decrease in the pancreatic islet mass, which is similar to the effects found in SEI-1 deficient mice. The KLF10-defect was also associated with the nuclear accumulation of the p21(Cip1) in islet cells. Based on our molecular and histological findings, we conclude that KLF10 plays an important role in pancreatic ß-cells and this supports a functional link between KLF10 and various cell cycle regulators, most notably in the context of the pancreas.