Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression

Choi, Byung-Min; Pae, Hyun‐Ock; Jeong, Young-Ran; Kim, Young‐Myeong; Chung, Hun‐Taeg

doi:10.1016/j.bbrc.2004.12.106

Cited by 134 publications

(112 citation statements)

References 19 publications

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“…HO-1 can modulate the immune response by inhibiting maturation of dendritic cells and by regulating the functions of Th1 and Treg cells [11][12][13]. To investigate whether the protective effect of transgenic mHo-1 works through these immunoregulatory functions, the mHo-1-transgenic NOD mice were crossed with T1/T2 double transgenic NOD mice to generate T1/T2/mHo-1 triple transgenic NOD mice.…”

Section: Resultsmentioning

confidence: 99%

“…Splenocytes from Ho-1 (also known as Hmox1) knockout mice secreted disproportionately high levels of Th1 cell-associated and proinflammatory cytokines on stimulation, implying a critical regulatory role of HO-1 in Th1/Th2 balance and early inflammatory responses [12]. In addition, Foxp3 and Ho-1 are coexpressed in human peripheral CD4 + CD25 + T regulatory (Treg) cells and the suppressive function of the cells is abrogated by inhibition of HO-1 activity [13]. Moreover, adeno-associated virusmediated overexpression of Ho-1 protected NOD mice from autoimmune diabetes by reducing the population of mature dendritic cells and autoreactive T lymphocytes, providing a successful preventive strategy for systemic Ho-1 expression in this disease [14].…”

Section: Introductionmentioning

confidence: 99%

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Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Huang

Chu²,

Yu³

et al. 2010

Diabetologia

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Aims/hypothesis Haem oxygenase 1 (HO-1) has strong anti-apoptotic, anti-inflammatory and antioxidative effects that help protect cells against various forms of immune attack. We investigated whether transgenic expression of Ho-1 (also known as Hmox1) in pancreatic beta cells would protect NOD mice from autoimmune damage and prolong graft survival following islet transplantation. Methods To evaluate the protective effect of beta cellspecific HO-1 in autoimmune diabetes, we used an insulin promoter-driven murine Ho-1 construct (pIns-mHo-1) to generate a transgenic NOD mouse. Transgene expression, insulitis and the incidence of diabetes in mice were characterised. Lymphocyte composition, the development of T helper (Th)1, Th2 and T regulatory (Treg) cells, T cell proliferation and lymphocyte-mediated disease transfer were analysed. The potential effects of transgenic islets and islet transplantation on apoptosis, inflammation and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) were evaluated. Results Transgenic mice showed less severe insulitis and a lower incidence of diabetes than non-transgenic control littermates. Lymphocyte composition and functions were not affected. Islets from transgenic mice expressed lower levels of proinflammatory cytokines/chemokines, proapoptotic gene expression and amounts of ROS/RNS, and were more resistant to TNF-α-and IFN-γ-induced apoptosis. Islet grafts from transgenic mice also survived longer in diabetic recipients than control islets. Conclusions/interpretation Transgenic overexpression of Ho-1 in beta cells protected NOD mice from diabetes and delayed the autoimmune destruction of islet grafts, providing valuable insight into the development of better strategies for clinical islet transplantation in patients with type 1 diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Huang

Chu²,

Yu³

et al. 2010

Diabetologia

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“…Interestingly, Choi et al [45] recently reported that foxp3 expression can induce HO-1 expression. Having found augmented foxp3 levels in mice receiving Treg transfer, we wondered whether HO-1 expression was augmented.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the pharmacological or gene therapy-based augmentation of HO-1 can rescue the pups from maternal rejection [43,44]. Furthermore, Choi et al [45] have recently reported that foxp3 expression can induce HO-1 expression. Thus, we wondered whether HO-1 expression was augmented at the fetal-maternal interface from animals receiving Treg, which had augmented foxp3 mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

et al. 2005

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The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-c and TNF-a were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-b and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.

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“…In some experimental models, wt FOXP3 has been shown to have an anti-proliferative effect. 22,47 However, downregulation of the FOXP3 splice forms had no effect on the spontaneous proliferation of the SeAx cells (Supplementary Figure 1), suggesting that the splice forms have no repressive effect on malignant proliferation. In support of this conclusion, Allan et al 21 showed that FOXP3D2 had little antiproliferative effect when expressed in transduced T cells relative to wt FOXP3.…”

Section: Discussionmentioning

confidence: 98%

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

et al. 2008

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Sé zary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-b and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-jB (NF-jB) activity in reporter assays which is in keeping with a constitutive NF-jB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.

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Critical role of heme oxygenase-1 in Foxp3-mediated immune suppression

Cited by 134 publications

References 19 publications

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Transgenic expression of haem oxygenase-1 in pancreatic beta cells protects non-obese mice used as a model of diabetes from autoimmune destruction and prolongs graft survival following islet transplantation

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

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