Anti-viral immune responses involve the robust production of type-I interferon (IFN-α/β) in plasmacytoid dendritic cells (pDCs). This occurs through the virus-activated MyD88-independent pathway, or ...the TLR7, 9/MyD88 pathways, and is completely dependent on the transcription factor IRF7 1. How type-I IFN is negatively regulated with respect to IRF7 remains unknown.Here we report that peroxisome proliferator-activated receptor gamma (PPAR-γ) is a negative-feedback regulator of IRF7-dependent TLR signaling for type-I IFN production.
WT and PPAR-γ (+/−) mice were used for in vitro stimulation of pDCs with TLR agonists, or i.v delivery of TLR agonists. Levels of type-I IFN in culture supernatants were assessed by ELISA. Interactions between IRF7 and PPAR-γ were studied by FLAG-IRF7 immunoprecipitation and Western blot analysis for PPAR-γ. Pristane (0.5 ml) was injected into WT and PPAR-γ (+/−) C57BL/6 to develop lupus-like disease, or control PBS. Interferon responses in mice were assessed by RT-PCR and ELISAs for autoantibodies.
Through TLR7, 9/MyD88 signaling in pDCs, type-I IFN induces the expression of PPAR-γ, which binds to the DNA-binding domain of IRF7, inhibiting IRF7 activation of type-I IFN genes. A critical role in vivo was confirmed in PPAR-γ (+/−) mice, which displayed enhanced TLR9-type-I IFN induction, compared to WT mice. Using the pristane-induced lupus model (TLR7/MyD88-type-IFN-dependent 2), disease in PPAR-γ (+/−) mice correlated with enhanced type-I IFN production/signaling, type-I IFN-dependent anti-nuclear antibody production and poor survival, compared to in WT mice. Pioglitazone (a PPAR-γ agonist) treatment inhibits murine lupus through a potent inhibitory effect on type-I IFN signaling.
Thus, the role of PPAR-γ in murine lupus, as a key regulator of type-I IFN production, provides a compelling argument for the therapeutic application of PPAR-γ agonists in human lupus, which is considered to be IFN-α-driven 3–5.
In this paper, I am looking for the common ground to judge video game’s formal qualities, such as its interface, the rule system and game goals, which would include and explain both intentionally and ...unintentionally subversive games labeled as ‘bad’ and ‘not games’. I start with two cases of games that subvert expectations to the degree when players actively refuse to recognize them as games. Such games have inspired a variety of research and critique, but there is surprisingly little agreement on what makes them “bad” or subversive, as opposed to typical genre-conforming violent games, which are supposed to be subversive or “bad” but rarely produce the same disruptive experience. Relying on existing analysis of subversive and violent games, I apply user-centered, goal-oriented approaches of UX design (Norman, 1998; Cooper, 2007) to games and complement this framework with a new category, ‘phantom affordances’: perceived formal properties of a game that actively afford an action but do not deliver the expected outcome. This category can be productively applied to describe and design subversions in games.
The antimalarial activities of some antifungal azole agents (ketoconazole, miconazole, and clotrimazole) have been known for several years, however, their antimalarial mechanism remains equivocal. ...Our recent study showed that clotrimazole has a relative high affinity for heme, inhibits reduced glutathione-dependent heme catabolism, and enhances heme-induced hemolysis. In the present study, we have found that clotrimazole can remove heme from histidine rich peptideheme complex, which initiates heme polymerization in malaria. In addition, we show that two other azoles (ketoconazole and miconazole) be have similarly to clotrimazole in binding to heme: they bind to heme with similar affinities, remove heme from the histidine rich peptide-heme complex and from the reduced glutathio one-heme complex to form stable heme-azole complexes with two nitrogenous ligands derived from the imidazole moieties of two azole molecules. We have also revealed that clotrimazole and miconazole have stronger promoting activities for heme-induced hemolysis than ketoconazole, implying that the stronger antimalarial activities of clotrimazole and miconazole might arise from their stronger ability to promote heme-induced hemolysis of clotrimazole and clotrimazole than that of ketoconazole. These results also suggest that ketoconazole and miconazole, like clotrimazole, might prossess an antimalarial mechanism relating to their inhibition of heme polymerization and the degradation of reduced glutathione-dependent heme.
Fatty Acids Suppress Autophagic Turnover in β-Cells Las, Guy; Serada, Sam B.; Wikstrom, Jakob D. ...
Journal of biological chemistry/The Journal of biological chemistry,
12/2011, Letnik:
286, Številka:
49
Journal Article
Recenzirano
Odprti dostop
Recent studies have shown that autophagy is essential for proper β-cell function and survival. However, it is yet unclear under what pathogenic conditions autophagy is inhibited in β-cells. Here, we ...report that long term exposure to fatty acids and glucose block autophagic flux in β-cells, contributing to their toxic effect. INS1 cells expressing GFP-LC3 (an autophagosome marker) were treated with 0.4 mm palmitate, 0.4 mm oleate, and various concentrations of glucose for 22 h. Kinetics of the effect of fatty acids on autophagy showed a biphasic response. During the second phase of autophagy, the size of autophagosomes and the content of autophagosome substrates (GFP-LC3, p62) and endogenous LC3 was increased. During the same phase, fatty acids suppressed autophagic degradation of long lived protein in both INS1 cells and islets. In INS1 cells, palmitate induced a 3-fold decrease in the number and the acidity of Acidic Vesicular Organelles. This decrease was associated with a suppression of hydrolase activity, suppression of endocytosis, and suppression of oxidative phosphorylation. The combination of fatty acids with glucose synergistically suppressed autophagic turnover, concomitantly suppressing insulin secretion. Rapamycin treatment resulted in partial reversal of the inhibition of autophagic flux, the inhibition of insulin secretion, and the increase in cell death. Our results indicate that excess nutrient could impair autophagy in the long term, hence contributing to nutrient-induced β-cell dysfunction. This may provide a novel mechanism that connects diet-induced obesity and diabetes.
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