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An octamer motif is required for activation of the inducible nitric oxide synthase promoter in pancreatic beta-cells.

Nitric oxide, generated by the inducible form of nitric oxide synthase (iNOS), is a potential mediator of cytokine-induced beta-cell dysfunction in type 1 diabetes mellitus. We have previously shown that cytokine-induced iNOS expression is cycloheximide (CHX) sensitive and requires nuclear factor-kappa B (NF-kappa B) activation. In the present study, we show that an octamer motif located 20 bp downstream of the proximal NF-kappa B binding site in the rat iNOS promoter is critical for IL-1 beta and interferon-gamma induction of promoter activity in rat primary beta-cells and insulin-producing RINm5F cells. In gel shift assays, the octamer motif bound constitutively the transcription factor Oct1. Neither Oct1 nor NF-kappa B binding activities were blocked by CHX, suggesting that other factor(s) synthesized in response to IL-1 beta contribute to iNOS promoter induction. The high mobility group (HMG)-I(Y) protein also bound the proximal iNOS promoter region. HMG-I(Y) binding was decreased in cells treated with CHX and HMG-I(Y) silencing by RNA interference reduced IL-1 beta-induced iNOS promoter activity. These results suggest that Oct1, NF-kappa B, and HMG-I(Y) cooperate for transactivation of the iNOS promoter in pancreatic beta-cells.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

RNase L and Double-Stranded RNA-Dependent Protein Kinase Exert Complementary Roles in Islet Cell Defense during Coxsackievirus Infection

Abstract Coxsackievirus (CV) is an important human pathogen that has been linked to the development of autoimmunity. An intact pancreatic β cell IFN response is critical for islet cell survival and protection from type 1 diabetes following CV infection. In this study, we show that IFNs trigger an antiviral state in β cells by inducing the expression of proteins involved in intracellular antiviral defense. Specifically, we demonstrate that 2′,5′-oligoadenylate synthetases (2-5AS), RNase L, and dsRNA-dependent protein kinase (PKR) are expressed by pancreatic islet cells and that IFNs (IFN-α and IFN-γ) increase the expression of 2-5AS and PKR, but not RNase L. Moreover, our in vitro studies uncovered that these pathways play important roles in providing unique and complementary antiviral activities that critically regulate the outcome of CV infection. The 2-5AS/RNase L pathway was critical for IFN-α-mediated islet cell resistance from CV serotype B4 (CVB4) infection and replication, whereas an intact PKR pathway was required for efficient IFN-γ-mediated repression of CVB4 infection and replication. Finally, we show that the 2-5AS/RNase L and the PKR pathways play important roles for host survival during a challenge with CVB4. In conclusion, this study has dissected the pathways used by distinct antiviral signals and linked their expression to defense against CVB4.</jats:p

The Role Played by Salts in the Formation of SBA-15, an in Situ Small-Angle X-ray Scattering/Diffraction Study

The influence of salts (NaCl, NaBr, and NaI) on the formation of mesoporous silica SBA-15 was studied in situ by small-angle X-ray scattering and diffraction. Pluronic P104 was used as structure director. The micellar properties and the dynamics of formation were clearly dependent on the presence of salt. It was also shown that the kinetics of mesophase formation, the initial value of the cell parameters, and the extent of long-range order were all influenced by salt additions. The observations are explained to primarily originate from the influence of the anions on the ethylene oxide part of the polymer, i.e., the corona region of the Pluronic micelles. Two effects are identified: a general ion effect causing dehydration of the ethylene oxide part and consequently inducing micellar growth, and a specific ion effect that counterbalances this. The study provides the basis for understanding the means by which addition of simple Na-salts influence the formation of mesoscopically ordered silicas synthesized using nonionic surfactants as structure directors, hence advancing the knowledge base toward a more rational design of mesoporous materials