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Intramural Papers of the Month

By Laura Hall and Emily Zhou
May 2010

PPAR gamma Protects Lungs against Inflammation and Oxidative Stress

NIEHS scientists and a collaborator from John Hopkins University have demonstrated that lung peroxisome proliferator activated receptor-gamma (PPARγ) has an essential role in protecting the lung against inflammation and oxidative injury. In this role, PPARγ is regulated by nuclear factor erythroid derived 2-like 2 (Nrf2).

Nrf2, a transcription factor, binds to antioxidant response elements (AREs) in the promoter regions of genes to induce antioxidant enzymes and defense proteins. Results from a microarray expression profiling study revealed that PPARγ induction in hyperoxia-susceptible Nrf2-deficient mice was decreased relative to that in wild-type mice. The researchers used a computational bioinformatic method to screen the promoter region of the PPARγ gene, Pparg, to find potential AREs for Nrf2 binding.

The researchers focused on the ARE that is 784 bases upstream of the PPARγ transciptional start site (-784 ARE). Deletion or mutation of this ARE site suppressed hyperoxia-induced Pparg promoter activity in airway epithelial cells overexpressing Nrf2. They determined that Nrf2 binding at the -784 promoter region is critical for hyperoxia-induced PPARγ expression

Animals dosed with PPARγ-specific interference RNA (siRNA) had increased hyperoxia-induced lung inflammation. In wild-type, but not Nrf2-deficient mice, dosing with a PPARγ ligand decreased hyperoxia-induced lung inflammation. The results show that  PPARγ activation protects against pulmonary oxidative injury.

Citation: Cho HY, Gladwell W, Wang X, Chorley B, Bell D, Reddy SP, Kleeberger SR.( Exit NIEHS 2010. Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. Am J Respir Crit Care Med March 11. [Epub ahead of print] doi:10.1164/rccm.200907-1047OC.

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Dust Mite Allergen Der p 7 Is Structurally Similar to Innate Immune Proteins

NIEHS researchers have determined the X-ray crystal structure and studied ligand binding of Der p 7, one of the allergenic proteins that comes from the house dust mite Dermatophagoides pteronyssinus.  The Der p 7  structure shows distant homology to a family of proteins involved in human immune recognition of bacterial lipid products.

Over 80 percent of asthmatic patients show hypersensitivity to house dust mite allergens. Greater than 50 percent of patients with dust mite allergy react specifically to Der p 7. However, how Der p 7 functions in the dust mite, why it causes allergic reaction in humans, and why it is associated with asthma are unknown.

The Der p 7 protein fold pattern of two four-stranded antiparallel beta-sheets that wrap around a long C-terminal helix is similar to that of lipopolysaccharide-binding protein (LBP). LBP promotes innate immune responses by transferring bacterially derived lipids to Toll-like receptors on the surface of immune cells.

The scientists demonstrated that Der p 7 does not bind lipopolysaccharide but does bind the bacterial lipopeptide polymyxin B (PB). PB binds with weak affinity in Der p 7's predicted binding site.  Many other allergens are known or predicted to bind lipid-like molecules.

The authors suggest that Der p 7 may act similarly to another dust mite allergen, Der p 2, and potentially interfere with normal innate host defense signaling through Toll-like receptors.

Citation: Mueller GA, Edwards LL, Aloor JJ, Fessler MB, Glesner J, Pomes A, et al.( Exit NIEHS 2010. The structure of the dust mite allergen Der p 7 reveals similarities to innate immune proteins J Allergy Clin Immunol 125(4):909-917.e4.

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Early-Life Exposures Are Linked to Development of Uterine Fibroids

Epidemiologists at NIEHS have, for the first time, linked soy formula during infancy, maternal prepregnancy diabetes, low childhood socioeconomic status, and early gestational age at birth to greater risk of early diagnosis of uterine leiomyomata (fibroids) in women.

Fibroids are benign smooth-muscle tumors, associated with pelvic pain, heavy bleeding, and reproductive problems. Fibroids are the most common indication for hysterectomies in the United States.

This study associated increased risk of fibroids diagnosed by age 35 with being fed soy formula during infancy. Infants fed only soy formula consume higher levels of isoflavones (predominantly genistein, which is estrogenically active) per unit body weight than adults consuming soy-based food. Neonatal treatment with genistein has been shown in animal studies to lead to development of uterine adenocarcinoma, abnormal mammary gland development and abnormal levels of estrogen and progesterone receptors in mammary glands, reduced fertility, and early reproductive senescence.

In addition, this is the first study to associate fibroids with maternal prepregnancy diabetes. The authors suggested that "one mechanism by which in utero exposure to diabetes would affect fibroid pathogenesis is the alteration of methylation patterns in regions that affect expression of relevant genes." One such gene is IGF2, whose expression levels were elevated in fibroids relative to normal myometrium in several microarray studies. 

Citation: D'Aloisio AA, Baird DD, DeRoo LA, Sandler DP.( Exit NIEHS 2010. Association of intrauterine and early-life exposures with diagnosis of uterine leiomyomata by 35 years of age in the sister study. Environ Health Perspect 118(3):375-81.

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Orphan G Protein-Coupled Receptor Mediates the Regulation of ERRa Gene Expression in Breast Cancer Cells

NIEHS researchers have demonstrated that activation of G protein-coupled estrogen receptor-1 (GPER-1) induces estrogen-related receptor alpha (ERRα) gene expression in an estrogen receptor (ER)-null breast cancer cell line. This induction causes modification of the chromatin structure of the ERRα promoter and recruitment of different transcription factors.

The ERRs share a high degree of sequence homology with ERs but do not bind estrogens or any other known natural ligand. ERRα belongs to a nuclear receptor subfamily that is ubiquitously and highly expressed in metabolically active tissues, suggesting a functional role in energy homeostasis. ERRa expression increases dramatically in ER-negative tumors and correlates with expression of a known marker for aggressive tumors. Deregulation of ERRα expression results in energy imbalance, leading to cancer, osteoporosis, and metabolic disorders.

This study shows the molecular mechanism underpinning the regulation of ERRα expression. ER agonists or antagonists activate GPER-1 to stimulate the pertussis toxin-sensitive Gαi subfamily of G proteins. This signaling event further triggers mitogen-activated protein kinase cascade, resulting in histone acetylation and transcription factor recruitment at the ERRα gene promoter.

The authors established a molecular mechanism that involves ERRα expression in aggressive breast cancers and provides insight into potential development of future therapeutic intervention for breast cancer progression.

Citation: Li, Y, Birnbaumer L, Teng CT.( Exit NIEHS 2010. Regulation of ERRα gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: Differential molecular mechanisms mediated by G Protein-Coupled Receptor GPR30/GPER-1. Mol Endocrinol 2010 March 8. [Epub ahead of print] doi:10.1210/me.2009-0148

(Laura Hall is a biologist in the NIEHS Laboratory of Toxicology and Pharmacology currently on detail as a writer for the Environmental Factor and Xixing (Emily) Zhou, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)

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