Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation

We identify the tumor necrosis factor receptor superfamily 25 (TNFRSF25)/TNFSF15 pair as critical trigger for allergic lung inflammation, which is a cardinal feature of asthma. TNFRSF25 (TNFR25) signals are required to exert T helper cell 2 (Th2) effector function in Th2-polarized CD4 cells and co-stimulate interleukin (IL)-13 production by glycosphingolipid-activated NKT cells. In vivo, antibody blockade of TNFSF15 (TL1A), which is the ligand for TNFR25, inhibits lung inflammation and production of Th2 cytokines such as IL-13, even when administered days after airway antigen exposure. Similarly, blockade of TNFR25 by a dominant-negative (DN) transgene, DN TNFR25, confers resistance to lung inflammation in mice. Allergic lung inflammation–resistant, NKT-deficient mice become susceptible upon adoptive transfer of wild-type NKT cells, but not after transfer of DN TNFR25 transgenic NKT cells. The TNFR25/TL1A pair appears to provide an early signal for Th2 cytokine production in the lung, and therefore may be a drug target in attempts to attenuate lung inflammation in asthmatics.

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Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-κB and c-Jun N-terminal kinase

Blood ◽

10.1182/blood-2003-01-0288 ◽

2003 ◽

Vol 102 (5) ◽

pp. 1740-1742 ◽

Cited By ~ 69

Author(s):

Ingrid Pollet ◽

Christy J. Opina ◽

Carla Zimmerman ◽

Kevin G. Leong ◽

Fred Wong ◽

...

Keyword(s):

Intracellular Signaling ◽

Tumor Necrosis Factor Receptor ◽

Nuclear Factor Κb ◽

Dominant Negative ◽

Bacterial Lipopolysaccharide ◽

Intracellular Signaling Pathway ◽

Necrosis Factor

AbstractThe intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor κB (NF-κB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-κB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)–induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.

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Allergic Lung Inflammation Is Mediated by Soluble Tumor Necrosis Factor (TNF) and Attenuated by Dominant-Negative TNF Biologics

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2010-0512oc ◽

2011 ◽

Vol 45 (4) ◽

pp. 731-739 ◽

Cited By ~ 16

Author(s):

Isabelle Maillet ◽

Silvia Schnyder-Candrian ◽

Isabelle Couillin ◽

Valerie F. J. Quesniaux ◽

Francois Erard ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Lung Inflammation ◽

Tumor Necrosis ◽

Dominant Negative ◽

Allergic Lung Inflammation ◽

Necrosis Factor

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Role of SODD in Regulation of Tumor Necrosis Factor Responses

Molecular and Cellular Biology ◽

10.1128/mcb.23.11.4026-4033.2003 ◽

2003 ◽

Vol 23 (11) ◽

pp. 4026-4033 ◽

Cited By ~ 35

Author(s):

Hidetoshi Takada ◽

Nien-Jung Chen ◽

Christine Mirtsos ◽

Shinobu Suzuki ◽

Nobutaka Suzuki ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Signaling Proteins ◽

Ligand Stimulation ◽

Cytotoxic Responses ◽

Necrosis Factor

ABSTRACT Signaling from tumor necrosis factor receptor type 1 (TNFR1) can elicit potent inflammatory and cytotoxic responses that need to be properly regulated. It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation. In this study, we demonstrate that mice lacking SODD produce larger amounts of cytokines in response to in vivo TNF challenge. SODD-deficient macrophages and embryonic fibroblasts also show altered responses to TNF. TNF-induced activation of NF-κB is accelerated in SODD-deficient cells, but TNF-induced c-Jun N-terminal kinase activity is slightly repressed. Interestingly, the apoptotic arm of TNF signaling is not hyperresponsive in the SODD-deficient cells. Together, these results suggest that SODD is critical for the regulation of TNF signaling.

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Apparently Normal Tumor Necrosis Factor Receptor 1 Signaling in the Absence of the Silencer of Death Domains

Molecular and Cellular Biology ◽

10.1128/mcb.23.18.6609-6617.2003 ◽

2003 ◽

Vol 23 (18) ◽

pp. 6609-6617 ◽

Cited By ~ 10

Author(s):

Robert Endres ◽

Georg Häcker ◽

Inge Brosch ◽

Klaus Pfeffer

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Death Receptor ◽

High Dose ◽

Wild Type ◽

Induced Apoptosis ◽

Necrosis Factor

ABSTRACT The silencer of death domains (SODD) has been proposed to prevent constitutive signaling of tumor necrosis factor receptor 1 (TNFR1) in the absence of ligand. Besides TNFR1, death receptor 3 (DR3), Hsp70/Hsc70, and Bcl-2 have been characterized as binding partners of SODD. In order to investigate the in vivo role of SODD, we generated mice congenitally deficient in expression of the sodd gene. No spontaneous inflammatory infiltrations were observed in any organ of these mice. Consistent with this finding, in the absence of SODD no alteration in the activation patterns of nuclear factor κB (NF-κB), stress kinases, or ERK1 or -2 was observed after stimulation with tumor necrosis factor (TNF). Activation of NF-κB by DR3 was also unchanged. The extents of DR3- and TNF-induced apoptosis were comparable in gene-deficient and wild-type cells. Protection of cells against heat shock as mediated by the Hsp70 system and against staurosporine-induced apoptosis was independent of SODD. Furthermore, resistance to high-dose lipopolysaccharide (LPS) injections, LPS-d-GalN injections, and infection with listeriae was similar in wild-type and gene-deficient mice. In conclusion, our data do not support the concept of a unique, nonredundant role of SODD for the functions of TNFR1, Hsp70, and DR3.

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Activation of the aryl hydrocarbon receptor is essential for mediating the anti-inflammatory effects of a novel low-molecular-weight compound

Blood ◽

10.1182/blood-2007-08-109645 ◽

2008 ◽

Vol 112 (4) ◽

pp. 1158-1165 ◽

Cited By ~ 77

Author(s):

B. Paige Lawrence ◽

Michael S. Denison ◽

Hermann Novak ◽

Beth A. Vorderstrasse ◽

Nathalie Harrer ◽

...

Keyword(s):

Molecular Weight ◽

Aryl Hydrocarbon Receptor ◽

Lung Inflammation ◽

Dominant Negative ◽

Low Molecular Weight ◽

Aryl Hydrocarbon ◽

Allergic Lung Inflammation ◽

Anti Inflammatory

Abstract VAF347 is a low-molecular-weight compound that inhibits allergic lung inflammation in vivo. This effect is likely the result of a block of dendritic cell (DC) function to generate proinflammatory T-helper (Th) cells because VAF347 inhibits interleukin (IL)–6, CD86, and human leukocyte antigen (HLA)–DR expression by human monocyte-derived DC, 3 relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein, resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biologic activity of VAF347 because (1) other AhR agonists display an identical activity profile in vitro, (2) gene silencing of wild-type AhR expression or forced overexpression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line, and (3) AhR-deficient mice are resistant to the compound's ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo.

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Reduced allergic lung inflammation and airway responsiveness in mice lacking the cytoskeletal protein gelsolin

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00065.2020 ◽

2020 ◽

Vol 319 (5) ◽

pp. L833-L842

Author(s):

Maya Mikami ◽

Gene T. Yocum ◽

Nicola M. Heller ◽

Charles W. Emala

Keyword(s):

Airway Inflammation ◽

Lung Inflammation ◽

Ex Vivo ◽

Cell Types ◽

Asthma Severity ◽

Wild Type ◽

Allergic Lung Inflammation ◽

Actin Capping

Airway smooth muscle hyperresponsiveness associated with chronic airway inflammation leads to the typical symptoms of asthma including bronchoconstriction and wheezing. Asthma severity is associated with airway inflammation; therefore, reducing airway inflammation is an important therapeutic target. Gelsolin is an actin capping and severing protein that has been reported to be involved in modulation of the inflammatory response. Using mice genetically lacking gelsolin, we evaluated the role of gelsolin in the establishment of house dust mite (HDM) antigen-induced allergic lung inflammation. The genetic absence of gelsolin was found to be protective against HDM sensitization, resulting in reduced lung inflammation, inflammatory cytokines, and Muc5AC protein in bronchoalveolar lavage (BAL) fluid. The number of eosinophils, lymphocytes, and interstitial macrophages in the BAL were increased after HDM sensitization in wild-type mice but were attenuated in gelsolin-null mice. The observed attenuation of inflammation may be partly due to delayed migration of immune cells, because the reduced eosinophils in the BALs from gelsolin-null mice compared with controls occurred despite similar amounts of the chemoattractant eotaxin. Splenic T cells demonstrated similar proliferation rates, but ex vivo alveolar macrophage migration was delayed in gelsolin-null mice. In vivo, the reduced lung inflammation after HDM sensitization in gelsolin-null mice was associated with significantly diminished airway resistance to inhaled methacholine compared with HDM-treated wild-type mice. Our results suggest that modulation of gelsolin expression or function in selective inflammatory cell types that modulate allergic lung inflammation could be a therapeutic approach for asthma.

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Mechanism for Removal of Tumor Necrosis Factor Receptor 1 from the Cell Surface by the Adenovirus RIDα/β Complex

Journal of Virology ◽

10.1128/jvi.79.21.13606-13617.2005 ◽

2005 ◽

Vol 79 (21) ◽

pp. 13606-13617 ◽

Cited By ~ 22

Author(s):

Y. Rebecca Chin ◽

Marshall S. Horwitz

Keyword(s):

Plasma Membrane ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Adaptor Protein ◽

Dominant Negative ◽

Sorting Motif ◽

Interfering Rna ◽

Necrosis Factor

ABSTRACT Proteins encoded in adenovirus early region 3 have important immunoregulatory properties. We have recently shown that the E3-10.4K/14.5K (RIDα/β) complex downregulates tumor necrosis factor receptor 1 (TNFR1) expression at the plasma membrane. To study the role of the RIDβ tyrosine sorting motif in the removal of surface TNFR1, tyrosine 122 on RIDβ was mutated to alanine or phenylalanine. Both RIDβ mutations not only abolished the downregulation of surface TNFR1 but paradoxically increased surface TNFR1 levels. RID also downregulates other death receptors, such as FAS; however, surface FAS expression was not increased by RIDβ mutants, suggesting that regulation of TNFR1 and that of FAS by RID are mechanistically different. In the mixing experiments, the wild-type (WT) RID-mediated TNFR1 downregulation was partially inhibited in the presence of RIDβ mutants, indicating that the mutants compete for TNFR1 access. Indeed, an association between RIDβ and TNFR1 was shown by coimmunoprecipitation. In contrast, the mutants did not affect the WT RID-induced downregulation of FAS. These differential effects support a model in which RID associates with TNFR1 on the plasma membrane, whereas RID probably associates with FAS in a cytoplasmic compartment. By using small interfering RNA against the μ2 subunit of adaptor protein 2, dominant negative dynamin construct K44A, and the lysosomotropic agents bafilomycin A1 and ammonium chloride, we also demonstrated that surface TNFR1 was internalized by RID by a clathrin-dependent process involving μ2 and dynamin, followed by degradation of TNFR1 via an endosomal/lysosomal pathway.

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P3442 In vivo inhibition of tumour necrosis factor-alpha reverses mitochondrial dysfunction in pacing-induced cardiomyopathy: Insights into role of cytokines and heart failure progression

European Heart Journal ◽

10.1016/s0195-668x(03)96068-4 ◽

2003 ◽

Vol 24 (5) ◽

pp. 665

Author(s):

J MARINGARCIA

Keyword(s):

Heart Failure ◽

Mitochondrial Dysfunction ◽

Tumour Necrosis ◽

Tumour Necrosis Factor Alpha ◽

Necrosis Factor Alpha ◽

Heart Failure Progression ◽

Factor Alpha ◽

Necrosis Factor

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TNFRSF14 deficiency protects against ovariectomy-induced adipose tissue inflammation

Journal of Endocrinology ◽

10.1530/joe-13-0341 ◽

2014 ◽

Vol 220 (1) ◽

pp. 25-33 ◽

Cited By ~ 10

Author(s):

Eun-Kyung Choi ◽

Woon-Ki Kim ◽

Ok-Joo Sul ◽

Yun-Kyung Park ◽

Eun-Sook Kim ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Adipose Tissue ◽

Tumor Necrosis ◽

Ovarian Function ◽

Tumor Necrosis Factor Receptor ◽

Oxygen Species ◽

Adipose Tissue Inflammation ◽

Metabolic Perturbation ◽

Necrosis Factor

To elucidate the role of tumor necrosis factor receptor superfamily member 14 (TNFRSF14) in metabolic disturbance due to loss of ovarian function, ovariectomy (OVX) was performed in TNFRSF 14-knockout mice. OVX increased fat mass and infiltration of highly inflammatory CD11c cells in the adipose tissue (AT), which was analyzed by flow cytometry, and resulted in disturbance of glucose metabolism, whereas TNFRSF14 deficiency attenuated these effects. TNFRSF14 deficiency decreased recruitment of CD11c-expressing cells in AT and reduced the polarization of bone marrow-derived macrophages to M1. Upon engagement of LIGHT, a TNFRSF14 ligand, TNFRSF14 enhanced the expression of CD11c via generation of reactive oxygen species, suggesting a role of TNFRSF14 as a redox modulator. TNFRSF14 participated in OVX-induced AT inflammation via upregulation of CD11c, resulting in metabolic perturbation. TNFRSF14 could be used as a therapeutic target for the treatment of postmenopausal syndrome by reducing AT inflammation.

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