Renal Hemodynamic, Inflammatory, and Apoptotic Responses to Lipopolysaccharide in HO-1−/− Mice

Tracz, Michał; Juncos, Julio P.; Grande, Joseph P.; Croatt, Anthony J.; Ackerman, Allan W.; Rajagopalan, Govindarajan; Knutson, Keith L.; Badley, Andrew D.; Griffin, Matthew D.; Alam, Jawed; Nath, Karl A.

doi:10.2353/ajpath.2007.061093

Cited by 67 publications

(67 citation statements)

References 59 publications

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“…35,36 Interestingly, both HO-1 as well as the product of its activity, CO, have been shown to inhibit activation of the NF-B pathway, [37][38][39] and CO has been shown to inhibit polyclonal T-cell proliferation in response to anti-CD3 and anti-CD28. 40 It is therefore possible that the induction of HO-1 during the early steps of DC activation may aid in the acquisition of a tolerogenic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Suppression by CD4+CD25+ Regulatory T Cells Is Dependent on Expression of Heme Oxygenase-1 in Antigen-Presenting Cells

George

Braun

Brusko

et al. 2008

The American Journal of Pathology

107

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Historically, heme oxygenase-1 (HO-1) has been viewed as a cytoprotective protein, ameliorating the effects of inflammatory cellular damage. The demonstration, however, of a beneficial role for HO-1 in allograft protection from acute and chronic rejection, 1-3 strongly suggests an important function of this enzyme in both innate and adaptive immune responses. In the original description of a mouse model of HO-1 deficiency, Poss and Tonegawa 4 noted an age-related overgrowth of the CD4 ϩ T-cell population, suggesting impaired regulation of T-cell proliferation. Our previous work assessing immune function in HO-1 Ϫ/Ϫ mice supported this notion because it showed a predominance of Th1-type cytokine secretion [eg, interleukin (IL)-1, interferon-␥, tumor necrosis factor-␣, IL-6] from splenocytes after polyclonal stimulation of T cells, implying that HO-1 activity is important in modulation of lymphocyte activation.5 This is of particular interest given reports that HO-1 is constitutively expressed in the CD4 ϩ CD25 ϩ subset of Treg cells, 6 and that HO-1 levels increase even further after T-cell stimulation.7 Furthermore, the report by Song and colleagues 8 demonstrated that carbon monoxide (CO), a byproduct of HO activity, has a very strong inhibitory effect on CD3-activated T-cell proliferation. Previously, we proposed a hypothetical model for the immunomodulatory effects of HO-1 in the maintenance of peripheral tolerance based on then available evidence that CO produced in regulatory T (Treg) cells may be an integral component of the suppression of T-cell activation by Treg cells in the presence of effector T (Teff) cells and antigen-presenting cells (APCs). 9The purpose of the present study was to analyze the role of HO-1 in Treg-mediated suppression. As a first step, we performed a phenotypic analysis of lymphocytes obtained from the peripheral lymphoid organs of HO-1 Ϫ/Ϫ mice for potential abnormalities. In the second step, we explored the functional significance of these findings in a series of T-cell proliferation/suppression assays. Finally, we examined the possibility that HO-1 exSupported by the National Institutes of Health (grants K08 AI 57362 to M.H.K., and R01 DK 075532 and R01 HL068157 to A.A).

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Section: Discussionmentioning

confidence: 99%

Suppression by CD4+CD25+ Regulatory T Cells Is Dependent on Expression of Heme Oxygenase-1 in Antigen-Presenting Cells

George

Braun

Brusko

et al. 2008

The American Journal of Pathology

107

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“…25,26) These studies suggest that HO-1 plays an important role in reducing the deleterious increase in oxidative damage. Srisook et al reported that both O 2 − and NO are related to HO-1 induction in macrophages by using an O 2 − generator and a NO donor.…”

Section: )mentioning

confidence: 99%

Nitric Oxide Is an Important Regulator of Heme Oxygenase-1 Expression in the Lipopolysaccharide and Interferon-γ-Treated Murine Macrophage-Like Cell Line J774.1/JA-4

et al. 2015

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1,2) Macrophages use a wide variety of pattern recognition receptors including Toll-like receptors (TLRs) that bind to these agents.3,4) Such receptors recognize various microbial components. 5) Once TLRs sense the presence of invading pathogens, their engagement with them activates macrophages, which then produce and release various sets of effector molecules aimed at destroying the foreign agents. Reactive oxygen species (ROS), such as superoxide anion (O 2 − ), hydrogen peroxide (H 2 O 2 ), and nitric oxide (NO), are their front line effector molecules.6-11) These highly diffusive products exert strong cytotoxic activities against micro-organisms and many neighboring cells, including against the macrophages themselves. However, macrophages and most of the aerobic host cells can protect themselves by enhancing the expression of heme oxygenase (HO). HO, a cellular antioxidant, is one of the key enzymes catalyzing the degradation of heme-containing molecules to biliverdin, free iron, and carbon monoxide.12,13) Three HO isozymes, including HO-1 (HSP32), HO-2, and HO-3, have been identified 14) ; although HO-3 may be a pseudo gene derived from HO-2 transcripts. 15)HO-1 is an inducible enzyme, whereas HO-2 is constitutive one.16) HO-1 is induced by various molecules and environmental factors, such as heme, radiation, cytokine, oxidative, and heat stresses. [17][18][19][20][21] Previous studies reported that lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, also induces the expression of both the HO-1 gene and its protein in macrophages.22-24) Exposure of HO-1-deficient mice to LPS leads to increased hepatocellular necrosis, increased splenic proinflammatory cytokine secretion, and higher mortality of septic shock when compared with wild-type animals. 25,26) These studies suggest that HO-1 plays an important role in reducing the deleterious increase in oxidative damage. Srisook et al. reported that both O 2 − and NO are related to HO-1 induction in macrophages by using an O 2 − generator and a NO donor. 27) However, it is not easy to study the role of O 2 − and NO separately in HO-1 induction in activated macrophages which produce both of these molecules simultaneously after LPS-treatment. Thus, among ROS, the important regulators of HO-1 in the activated macrophages have not been clear. The aim of the present work was to identify the regulator of HO-1 induction in activated macrophages. In this study, we sought to identify the regulator of HO-1 induction of the activated macrophages by using 2 types of macrophages, i.e., cells of the murine macrophage-like cell line J774.1/JA-4 and their LPS-resistant mutant, LPS1916. 7) This mutant cell line is characterized by a specific defect in the induction of ROS after LPS treatment. Our recent study reported that LPS1916 cells have the phenotype of mal-expression of CD14, a key molecule required for LPS-induced activation of cells, on the macrophage cell surface, leading to reduced responses to LPS. 28) Interestingly, this defect i...

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“…[25][26][27][28][29] Colonies of mice were maintained by breeding HO-1 Ϫ/Ϫ males with HO-1 ϩ/Ϫ females. Offspring were genotyped at the time of weaning using PCR to amplify the wild-type and mutant alleles of genomic DNA from tail samples.…”

Section: Methodsmentioning

confidence: 99%

Induction of Heme Oxygenase-1 is a Beneficial Response in a Murine Model of Venous Thrombosis

Tracz

Juncos

Grande

et al. 2008

The American Journal of Pathology

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؊/؊ mice exhibited increased nuclear factor B activation and markedly increased up-regulation of tissue factor, selectins, inflammatory cytokines, and matrix metalloproteinase-9, the latter incriminated in both clot lysis and vascular injury. We conclude that HO-1 deficiency impairs thrombus resolution and exaggerates the inflammatory response to thrombus formation. These findings offer insight into recent observations that polymorphisms in the HO-1 gene may increase the risk for recurrent venous thrombosis and dysfunction of hemodialysis arteriovenous fistulas, the latter caused, in part, by thrombosis.

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Renal Hemodynamic, Inflammatory, and Apoptotic Responses to Lipopolysaccharide in HO-1−/− Mice

Cited by 67 publications

References 59 publications

Suppression by CD4+CD25+ Regulatory T Cells Is Dependent on Expression of Heme Oxygenase-1 in Antigen-Presenting Cells

Suppression by CD4+CD25+ Regulatory T Cells Is Dependent on Expression of Heme Oxygenase-1 in Antigen-Presenting Cells

Nitric Oxide Is an Important Regulator of Heme Oxygenase-1 Expression in the Lipopolysaccharide and Interferon-γ-Treated Murine Macrophage-Like Cell Line J774.1/JA-4

Induction of Heme Oxygenase-1 is a Beneficial Response in a Murine Model of Venous Thrombosis

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