Heme Oxygenase-1 Regulates Dendritic Cell Function through Modulation of p38 MAPK-CREB/ATF1 Signaling

Al-Huseini, Laith M Abbas; Yeang, Han Xian Aw; Hamdam, Junnat; Sethu, Swaminathan; Alhumeed, Naif; Wong, Wai Keong; Sathish, Jean G.

doi:10.1074/jbc.m113.532069

Cited by 53 publications

(49 citation statements)

References 51 publications

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“…It was recently found that MAPKs play an important role in regulating DC maturation [39]. They can also influence the function of the T cell response during antigen presentation [40].…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways

Jiang

Xia

et al. 2018

Int Arch Allergy Immunol

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Smoking is considered to be the main source of indoor pollution, and it has been identified as an important environmental factor contributing to asthma onset. We know that T helper 2 (Th2) response plays a crucial role in the process of asthma disease. We have investigated the reaction of cigarette smoke extract (CSE) on Th polarization which is controlled by dendritic cells (DCs). Stimulated by CSE, immature DCs from murine bone marrow showed upregulated levels of TIM4. Cocultured with CD4+ T cells, stimulated DCs increased the ratio of IL-4+ versus IFN-γ+ of CD4+ T cells. This suggests a differentiation towards Th2 response. Moreover, antibodies against TIM4 reversed the upexpression of the IL-4+/IFN-γ+ ratio provoked by CSE, indicating that the Th2 polarization which was induced by CSE is via TIM4 mechanisms. CSE could activate mitogen-activated protein kinase pathways like ERK and p38. Upregulation of TIM4 expression by CSE stimulation was found to be inhibited by an ERK inhibitor but not p38 and JNK. In conclusion, DC-induced Th2 polarization is a hallmark of CSE allergy, and this aspect can be explained by CSE-induced TIM4 expression.

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“…It was recently found that MAPKs play an important role in regulating DC maturation [39]. They can also influence the function of the T cell response during antigen presentation [40].…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways

Jiang

Xia

et al. 2018

Int Arch Allergy Immunol

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“…[2][3][4][5] A large number of studies have shown that HO-1 played extensive protective roles in inflammatory diseases such as asthma, 4,[6][7][8][9] inflammatory bowel disease [10][11][12][13] and uveitis. 14,15 In addition, HO-1 exerts its effects on multiple immune cells, such as promoting maturation, differentiation and function of dendritic cells, 16,17 inhibiting the antigen-presenting function of dendritic cells, 18 inducing tolerance of dendritic cells 19 and suppressing degranulation of mast cells. 20,21 In previous studies, HO-1 was found to enhance the function of CD4 + CD25 + regulatory T cells.…”

Section: Introductionmentioning

confidence: 99%

Heme oxygenase‐1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2‐mediated allergic airway inflammation

Zhong¹,

et al. 2016

Immunology

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SummaryThe anti-inflammatory role of heme oxygenase-1 (HO-1) has been studied extensively in many disease models including asthma. Many cell types are anti-inflammatory targets of HO-1, such as dendritic cells and regulatory T cells. In contrast to previous reports that HO-1 had limited effects on basophils, which participate in T helper type 2 immune responses and antigeninduced allergic airway inflammation, we demonstrated in this study, for the first time, that the up-regulation of HO-1 significantly suppressed the maturation of mouse basophils, decreased the expression of CD40, CD80, MHC-II and activation marker CD200R on basophils, blocked DQ-ovalbumin uptake and promoted basophil apoptosis both in vitro and in vivo, leading to the inhibition of T helper type 2 polarization. These effects of HO-1 were mimicked by exogenous carbon monoxide, which is one of the catalytic products of HO-1. Furthermore, adoptive transfer of HO-1-modified basophils reduced ovalbumin-induced allergic airway inflammation. The above effects of HO-1 can be reversed by the HO-1 inhibitor Sn-protoporphyrin IX. Moreover, conditional depletion of basophils accompanying hemin treatment further attenuated airway inflammation compared with the hemin group, indicating that the protective role of HO-1 may involve multiple immune cells. Collectively, our findings demonstrated that HO-1 exerted its anti-inflammatory function through suppression of basophil maturation and activation, but promotion of basophil apoptosis, providing a possible novel therapeutic target in allergic asthma.

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“…However, tumor necrosis factor alpha (TNF-␣) was shown to increase HO-1 protein levels in the Caco-2 cell line, and Nrf2 suppression did not affect TNF-␣-induced HO-1 protein expression in these cells (37). Although MAPK signaling is important for HO-1 expression (11,38,39), there is no evidence of BFT-induced MAPK and NF-B activation leading to HO-1 expression. In the present study, pretreatment of primary intestinal epithelial cells with the p38 inhibitor SB203580 was superior to treatment with the ERK inhibitor PD98059 or the JNK inhibitor SP600125 at inhibiting HO-1 expression.…”

Section: Discussionmentioning

confidence: 91%

Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis

Rho

Jeon

et al. 2016

Infect Immun

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Enterotoxigenic Bacteroides fragilis (ETBF) is associated with noninvasive diarrheal diseases (1, 2), inflammatory bowel diseases (1), and colorectal cancers (3-5). B. fragilis enterotoxin (BFT), a virulence factor of ETBF, is responsible for these diseases (1). BFT interacts with a single layer of intestinal epithelial cells and can provoke signals that induce mucosal inflammation (1, 6-9).In mammalian cells, two genetically distinct isozymes of heme oxygenase (HO) have been clearly identified. HO-1 is inducible, whereas HO-2 is constitutively expressed. HO-1 catalyzes the degradation of free heme into carbon monoxide, biliverdin, and free iron (10, 11). Within mammalian cells, biliverdin reductase converts biliverdin to bilirubin. Pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), lipoteichoic acid, and peptidoglycan, as well as several proinflammatory cytokines, can induce HO-1 expression (12). Upregulated HO-1 expression can lead to adaptive immune responses that protect cells from immunopathogenesis or stress damage (12, 13). In addition, HO-1 expression is involved in clearance of pathogenic bacteria and downregulation of inflammatory responses. For example, HO-1 deficiency not only results in inadequate pathogen clearance (14) but also promotes the development of necrotizing enterocolitis-like intestinal injury in mice (15). HO-1 and HO-1-induced carbon monoxide can ameliorate intestinal inflammation through promotion of bacterial clearance (16). The HO-1/carbon monoxide pathway also suppresses Toll-like receptor 4 (TLR4) signaling, leading to downregulation of proinflammatory signaling induced by stimulation with LPS (17). Based on these findings, we hypothesized that the induction of HO-1 may regulate inflammatory responses induced by BFT. However, there are no reports regarding BFT-induced HO-1 expression.Signals from transcription factors, including nuclear factor-B (NF-B), activator protein-1 (AP-1), and NF-E2-related factor 2 (Nrf2, or nuclear factor [erythroid-derived 2]-like 2 [NFE2L2]), regulate the expression of HO-1 (11). Stimulation of intestinal epithelial cells with BFT can activate NF-B and AP-1 signaling (6)(7)(8)(9)(18)(19)(20). We have previously demonstrated that exposure of intestinal epithelial cells to BFT results in delayed apoptosis, suggesting that protection of cells after BFT stimulation is related to the generation of signals that activate or suppress mucosal inflammation (21). These observations raise the possibility that signaling molecules that regulate HO-1 expression may be activated in BFTexposed cells. However, there is no evidence that BFT-induced signaling results in HO-1 induction in intestinal epithelial cells. We therefore investigated HO-1 induction in response to stimulation of intestinal epithelial cells with BFT. We found that a signaling pathway involving p38 mitogen-activated protein kinases (MAPKs)-IB kinase (IKK)-NF-B in intestinal epithelial cells is required for HO-1 induction following exposure to BFT.

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Heme Oxygenase-1 Regulates Dendritic Cell Function through Modulation of p38 MAPK-CREB/ATF1 Signaling

Cited by 53 publications

References 51 publications

Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways

Cigarette Smoke Extract Promotes TIM4 Expression in Murine Dendritic Cells Leading to Th2 Polarization through ERK-Dependent Pathways

Heme oxygenase‐1 inhibits basophil maturation and activation but promotes its apoptosis in T helper type 2‐mediated allergic airway inflammation

Bacteroides fragilis Enterotoxin Upregulates Heme Oxygenase-1 in Intestinal Epithelial Cells via a Mitogen-Activated Protein Kinase- and NF-κB-Dependent Pathway, Leading to Modulation of Apoptosis

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