Kruppel-like factor 6 (KLF6) is a tumor suppressor gene inactivated in prostate and colon cancers, as well as in astrocytic gliomas. Here, we establish that KLF6 mediates growth inhibition through an interaction with cyclin D1, leading to reduced phosphorylation of the retinoblastoma protein (Rb) at Ser 795 . Furthermore, introduction of KLF6 disrupts cyclin D1-cyclin-dependent kinase (cdk) 4 complexes and forces the redistribution of p21Cip/Kip onto cdk2, which promotes G 1 cell cycle arrest. Our data suggest that KLF6 converges with the Rb pathway to inhibit cyclin D1/cdk4 activity, resulting in growth suppression.

Primary biliary cirrhosis (PBC) is characterized by loss of tolerance against ubiquitously expressed mitochondrial autoantigens followed by biliary and salivary gland epithelial cell (BEC and SGEC) destruction by autoreactive T cells. It is unclear why BECs and SGECs are targeted. Previous work demonstrated that the reduced form of the major PBC autoantigen predominated in apoptotic BECs and SGECs as opposed to an oxidized form in other apoptotic cells. This led to the hypothesis that presentation of novel self-peptides from phagocytosed apoptotic BECs might contribute to BEC targeting by autoreactive T cells. The effect of autoantigen redox status on self-peptide formation was examined along with the phagocytic ability of BECs. Oxidation of PBC autoantigens first was shown to be due to protein S-glutathionylation of lipoyllysine residues. Absence of protein S-glutathionylation generated novel self-peptides and affected T cell recognition of a lipoyllysine containing peptide. Liver biopsy staining revealed BEC phagocytosis of apoptotic BECs (3.74+/-2.90% of BEC) was present in PBC (7 of 7 cases) but not in normal livers (0 of 3). BECs have the ability to present novel mitochondrial self-peptides derived from phagocytosed apoptotic BECs. Apoptotic cell phagocytosis by non-professional phagocytes may influence the tissue specificity of autoimmune diseases.

Due to increased obesity, non-alcoholic fatty liver disease (NAFLD) is now the most prevalent liver disease in the United States. NAFLD is considered a component of metabolic syndrome, a cluster of disorders that also includes diabetes mellitus, dyslipidemia, arteriosclerosis, and hypertension. Exposure to ambient air particulate matter with aerodynamic diameters < 2.5 µm (PM 2.5 ) is a risk factor for arteriosclerosis as well as lung disease, but its effect on NAFLD is unknown. PM 2.5 induces pulmonary dysfunction via toll-like receptor activation on alveolar macrophages. Toll-like receptor activation of Kupffer cells, resident hepatic macrophages, and subsequent pro-inflammatory cytokine production have been shown to play a key role in NAFLD progression. We hypothesized that PM 2.5 exposure is a significant risk factor for progression of NAFLD. Thus, following exposure of male C57BL/6 mice fed high fat chow to concentrated air particulate matter (CAPs) or filtered air for 6 wk, progression of NAFLD was evaluated by standardized histological assessment of hepatic inflammation and fibrosis. In mice fed high fat chow, the hepatic inflammatory grade (3.00 ± 0.00 vs. 1.50 ± 0.71, p < 0.001) and fibrosis stage (1.00 ± 0.00 vs. 0.60 ± 0.52, p = 0.023) were both significantly higher in mice exposed to CAPs versus filtered air, respectively. Increased numbers of Kupffer cells contained PM in CAPsexposed mice (2.00 ± 0.94 vs. 0.20 ± 0.42, respectively, p < 0.001). PM exposure increased IL-6 secretion up to seven fold in a dose-dependent manner by isolated wild-type but not TLR4 −/− Kupffer cells (p < 0.050). Conclusion: Ambient PM 2.5 exposure may be a significant risk factor for NAFLD progression.

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Background The use of nanoparticles (NPs) in technological applications is rapidly expanding, but the potential health effects associated with NP exposure are still largely unknown. Given epidemiological evidence indicating an association between inhaled ambient ultrafine particles and increased risk of cardiovascular disease morbidity and mortality, it has been suggested that exposure to NPs via inhalation may induce similar cardiovascular responses. Methods Male C57BL/6 mice were exposed via whole-body inhalation to either filtered air (FA) or nickel hydroxide (NH) NPs (100, 150, or 900 μg/m3) for 1, 3, or 5 consecutive days (5 h/day). At 24-h post-exposure, vascular function in response to a vasoconstrictor, phenylephrine (PE), and a vasodilator, acetylcholine (ACh), was measured in the carotid artery. Results Carotid arteries from mice exposed to all concentrations of NH-NPs showed statistically significant differences in graded doses of PE-induced contractile responses compared with those from FA mice. Similarly, vessels from NH-NP-exposed mice also demonstrated impaired vasorelaxation following graded doses of ACh as compared with FA mice. Conclusions These results suggest that short-term exposure to NH-NPs can induce acute endothelial disruption and alter vasoconstriction and vasorelaxation. These findings are consistent with other studies assessing vascular tone and function in the aorta, coronary, and mesenteric vessels from mice exposed to motor vehicular exhaust and concentrated ambient particles.