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Intramural papers of the month

By Robin Arnette and Jeffrey Stumpf
September 2010

The absence of SIRT1 produces an inflammatory response

NIEHS scientists have determined that SIRT1, a member of the NAD+-dependent deacetylase family of proteins called sirtuins, provides protection against chronic inflammation by controlling the acetylation of nuclear factor kappa B (NF-κB), a transcription signaling pathway involved in the innate immune response. The finding may lead to treatment therapies for chronic inflammatory conditions such as obesity, insulin resistance, and type 2 diabetes.

For its in vivo work, the research team generated a myeloid-specific SIRT1 knockout mouse model (Mac-SIRT1 KO) and demonstrated that the absence of SIRT1 resulted in hyperacetylated NF-κB, which led to an increase in the transcription of proinflammatory genes in macrophages. When the Mac-SIRT1 KO mice were fed a high-fat diet, their liver and fat tissue displayed an increased amount of macrophage infiltration. This condition predisposed the mice to the development of systemic insulin resistance.

Using bone marrow-derived macrophages from wild-type and Mac-SIRT1 KO, the investigators confirmed their results in vitro. The Mac-SIRT1 KO cells also exhibited hyperacetylated NF-κB levels. Taken together, these data show that SIRT1is an important mediator between environmental stress and immune system activation.

Citation: Schug TT, Xu Q, Gao H, Peres-da-Silva A, Draper DW, Fessler MB, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20647536) Exit NIEHS 2010. Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Mol Cell Biol. Epub ahead of print. doi:10.1128/MCB.00657-10

Dyslipidemia and the TLR response

Dyslipidemia, an abnormal amount or quality of fats in the blood, induces opposite effects on host defense, depending on whether infection occurs inside the lung or elsewhere in the body. A new NIEHS-funded study - performed by investigators from NIEHS, the National Heart, Lung and Blood Institute, the University of Vermont College of Medicine, and Wake Forest University - represents the first published in vivo evidence that macrophages have increased surface expression of lipid rafts and TLR4, the lipopolysaccharide (LPS) receptor, during dyslipidemia.

Following inhalation of either LPS or K. pneumoniae, neutrophil recruitment to and cytokine induction in the airspace were both attenuated in dyslipidemic mice, and clearance of bacteria from the lung was impaired. In contrast, the researchers found that during dyslipidemia bacteria were cleared more efficiently from the bloodstream and peritoneum, due to more robust inflammatory responses in these body compartments.

Macrophages from the peritoneum, in which cholesterol levels increased during dyslipidemia, had increased lipid rafts associated with increased TLR4 expression and function. By contrast, macrophages from the airspace, in which cholesterol was maintained at a constant level during dyslipidemia, had normal responses and rafts. Taken together, the data suggest that the airspace may be a privileged immune site, thereby uniquely sensitive to the effects of dyslipidemia.

Citation: Madenspacher JH, Draper DW, Smoak KA, Li H, Griffiths GL, Suratt BT, et al. (http://www.ncbi.nlm.nih.gov/pubmed/20581153) Exit NIEHS 2010. Dyslipidemia induces opposing effects on intrapulmonary and extrapulmonary host defense through divergent TLR response phenotypes. J Immunol 185(3):1660-1669.

Cohesin prevents genome instability by restricting DNA repair to sister chromatids

NIEHS researchers have reported that reduction in yeast sister chromatid cohesion complex, or cohesin, decreased survival and permitted recombination between homologous chromosomes when exposed to low level radiation. While supporting current models in which the tethering of sister chromatids together following replication promoted DNA double-strand break repair via recombination, they showed that cohesin was limiting and that a small reduction placed the cell at risk for inappropriate recombination.

This study utilized an innovative method of decreasing protein amounts by maintaining only one copy of the essential cohesin subunit gene MCD1 in tetraploid yeast strain, thereby causing a three- to four-fold reduction as compared to wildtype tetraploid strains. This approach provided the opportunity to assess essential gene products under conditions of natural gene regulation and enabled the impact of variation in protein levels on cellular function to be addressed.

Restraining homologous recombination to copies of the same sequence in sister chromatids effectively protects genomic stability in response to DNA breaks. However, this study demonstrated that when the cohesin level was reduced, opportunities for recombination between homologous sequences across the genome were increased, which can lead to nonallelic recombination and rearrangements, as well as loss of heterozygosity. These types of genetic instabilities are important in the etiology of some genetic disorders and cancers.

Citation: Covo S, Westmoreland JW, Gordenin DA, Resnick MA. (http://www.ncbi.nlm.nih.gov/pubmed/20617204) Exit NIEHS 2010. Cohesin is limiting for the suppression of DNA damage-induced recombination between homologous chromosomes. PLoS Genet 6(7):e1001006.

Oxidized (bi)sulfite leads to reactive sulfur species and protein radical formation

A recent study by NIEHS researchers published in the July issue of Environmental Health Perspectives provides evidence that sulfite and (bi)sulfite, commonly used as food preservatives, can be oxidized into reactive free radicals that result in protein oxidative damage. Oxidative damage is proposed to lead to tissue injury in allergic reactions due to byproducts of sulfur dioxide.

Sulfite and (bi)sulfite are two ionized forms of the major pollutant sulfur dioxide that are used to prevent food spoilage. Using electron paramagnetic resonance, optical spectroscopy, oxygen uptake, and immune-spin trapping, the investigators were able to show that the oxidase activity of copper, zinc-superoxide dismutase oxidizes (bi)sulfite into the reactive sulfur species peroxymonosulfate anion radical and sulfate anion radical.

(Bi)sulfite is approved by the FDA, despite its association with allergies, asthma, and anaphylactic shock. Mechanisms for (bi)sulfite toxicity have been unclear. However, deficiencies in the mitochondrial enzyme sulfite oxidase cause abnormally high levels of sulfite in plasma resulting in toxicity. This study reports that protein damage by free radical formation caused by oxidized (bi)sulfite should be considered as a possible cause for (bi)sulfite toxicity.

Citation: Ranguelova K, Bonini MG, Mason RP. (http://www.ncbi.nlm.nih.gov/pubmed/20348042) Exit NIEHS 2010. (Bi)sulfite oxidation by copper, zinc-superoxide dismutase: Sulfite-derived, radical-initiated protein radical formation. Environ Health Perspect 118(7):970-975.

(Jeffrey Stumpf, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Mitochondrial DNA Replication Group.)



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