Published online before print November 8, 2007

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(American Journal of Pathology. 2007;171:1904-1914.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070096

Heme Oxygenase-1 Attenuates Ovalbumin-Induced Airway Inflammation by Up-Regulation of Foxp3 T-Regulatory Cells, Interleukin-10, and Membrane-Bound Transforming Growth Factor-β1

Zhen-Wei Xia^*, Li-Qing Xu^*, Wen-Wei Zhong^*, Jing-Jing Wei^*, Ning-Li Li, Jie Shao^*, Yun-Zhu Li^*, Shan-Chang Yu^* and Zi-Li Zhang

From the Department of Pediatrics,^* Ruijin Hospital, School of Medicine, and the Shanghai Immunology Institute, Shanghai Jiaotong University, Shanghai, China; and the Department of Pediatrics, Oregon Health and Science University, Portland, Oregon

Cumulative evidence suggests the up-regulation of interleukin (IL)-10 and T-regulatory (Treg) cells is implicated in anti-inflammatory effect of heme oxygenase-1 (HO-1). Thus, we postulated that induction of HO-1 could augment IL-10 and transforming growth factor (TGF)-β production and foxp3⁺CD4⁺CD25⁺ Treg cell function, thereby leading to attenuation of airway inflammation. In this study, CD4⁺CD25⁺ Treg cells isolated from mouse spleen were either transfected with a HO-1 expression vector (pcDNA3HO-1) or treated with a HO-1 inducer (hemin). Up-regulation of HO-1 enhanced foxp3 expression and IL-10 secretion in the Treg cells in vitro. Next, BALB/c, C57/B6.129, and IL-10-deficient B6.129P2-Il10^tm1Cgn/J mice were challenged by ovalbumin to induce airway inflammation. Consistent with in vitro findings, hemin treatment resulted in induction of HO-1 and foxp3 and production of IL-10 and membrane-bound TGF-β1 in vivo. This was further correlated with decrease of ovalbumin-specific immunoglobulin E level and eosinophil infiltration in bronchial alveolar lavage fluid from the asthmatic mice. Furthermore, hemin significantly enhanced the biological activity of CD4⁺CD25⁺ Treg cells. This protective effect was specifically blocked by Sn-protoporphyrin, a HO-1 enzymatic inhibitor. Finally, hemin failed to up-regulate the function of CD4⁺CD25⁺ Treg cells from IL-10-deficient mice. Our study indicates that HO-1 exerts its protective effect on asthma through a mechanism mediated by foxp3⁺CD4⁺CD25⁺ Treg cells, IL-10, and membrane-bound TGF-β1.

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