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Published ahead of print on October 5, 2009
Am. J. Respir. Cell Mol. Biol. 2009, doi:10.1165/rcmb.2008-0438OC
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Submitted on November 11, 2008
Accepted on October 1, 2009

Nrf2 Inhibits the Maturation of Murine Dendritic Cells by Ragweed Extract

Tirumalai Rangasamy1, Marc A Williams2, Stephen Bauer3, Michael A Trush4, Jason Emo4, Steve N Georas2, and Shyam Biswal5*

1 Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, United States; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States, 2 Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States; Division of Pulmonary and Critical Care, University of Rochester Medical Center, Rochester, New York, United States, 3 Division of Pulmonary and Critical Care, University of Rochester Medical Center, Rochester, New York, United States, 4 Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, United States, 5 Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, United States; Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, United States

* To whom correspondence should be addressed. E-mail: sbiswal{at}jhsph.edu.

Oxidative stress plays an important role in immune regulation and dendritic cell (DC) maturation. Recent studies indicate that allergens including ragweed extract (RWE) possess pro-oxidant activities, but how RWE interacts with DC is not well understood. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a key transcription factor that regulates constitutive as well as coordinated induction of a battery of antioxidant genes. We hypothesized that RWE would activate DC’s, and that this response would be augmented in the absence of Nrf2. We generated bone marrow-derived DCs (BM-DC) and isolated lung DC from Nrf2+/+ and Nrf2-/- mice and studied the effects of RWE on DC in vitro. Under resting conditions, Nrf2-/- BM-DC exhibited constitutively greater levels of inflammatory cytokines and costimulatory molecules than Nrf2+/+ BM-DC. Exposure to RWE impaired endocytic activity, significantly induced oxidative stress and enhanced the expression of CD80, CD86 and MHCII in Nrf2-/- BM-DC when compared to Nrf2+/+ BM-DC, in association with reduced expression of Nrf2 regulated antioxidant genes. RWE significantly induced the secretion of inflammatory cytokines IL-6 and TNF{alpha} in both BM-DC and lung DC from Nrf2-/- mice than Nrf2+/+ mice and significantly inhibited the secretion of IL-12 in Nrf2+/+ BM-DC and IL-18 in both Nrf2+/+ and Nrf2-/- BM-DC. The stimulatory effects of RWE on DC activation were inhibited to varying degrees by the antioxidant N-acetyl cysteine. Our findings indicate that a defect in Nrf2 mediated signaling mechanisms alters the response of DC to a common environmental allergen, which may contribute to the susceptibility to allergic diseases.
Key words: Nrf2 • Dendritic cells • Ragweed extract • Antioxidant genes • Oxidative stress






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