Heme oxygenase-1 attenuates ovalbumin-induced airway inflammation by up-regulation of foxp3 T-regulatory cells, interleukin-10, and membrane-bound transforming growth factor- 1.
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)-beta 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-Il10tm1Cgn/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-beta1 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-beta1.
Xia
Zhen-Wei
ZW
Department of Pediatrics, Ruijin Hospital, Ruijin 2nd Rd. 197, Shanghai 200025, China. xzw63@hotmail.com
Xu
Li-Qing
LQ
Zhong
Wen-Wei
WW
Wei
Jing-Jing
JJ
Li
Ning-Li
NL
Shao
Jie
J
Li
Yun-Zhu
YZ
Yu
Shan-Chang
SC
Zhang
Zi-Li
ZL
D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology*; D015704:CD4 Antigens / Q000032:analysis; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007073:Immunoglobulin E / Q000097:blood; D007249:Inflammation / Q000201:enzymology / Q000276:immunology; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008168:Lung / Q000201:enzymology; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010047:Ovalbumin / Q000276:immunology; D011524:Protoporphyrins / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000097:blood / Q000378:metabolism
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008665:Metalloporphyrins; D011524:Protoporphyrins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007073:Immunoglobulin E; D006427:Hemin; D010047:Ovalbumin; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1