The soluble glucocorticoid-induced tumor necrosis factor receptor causes cell cycle arrest and apoptosis in murine macrophages

Shin, Hong Ju; Kim, Soojin; Lee, Hee-Sook; Choi, Hye-Seon

doi:10.1016/j.bbrc.2004.02.012

Cited by 20 publications

(19 citation statements)

References 37 publications

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“…Because macrophages express both GITR and GITRL, the increased expression of GITR may both positively modulate GITR-mediated pathways and trigger GITRL. In fact, recent studies demonstrate that GITRL can activate cytoplasmic signals following GITR binding (8,13,14,16,42). Future studies will clarify whether these mechanisms are both crucial in determining the decreased response of GITR Ϫ/Ϫ mice to carrageenan treatment.…”

Section: Discussionmentioning

confidence: 95%

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Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

Cuzzocrea

Nocentini

Paola

et al. 2006

The Journal of Immunology

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Glucocorticoid-induced TNFR-related gene (GITR) participates in the immune/inflammatory response. Because GITR expression has been described in cells other than T lymphocytes, we investigated whether it also modulates acute inflammatory response. Using GITR-deficient (GITR−/−) mice, we analyzed the role of GITR in the development of carrageenan-induced lung inflammation (pleurisy) by studying several proinflammatory markers 2–8 h after carrageenan injection. When compared with GITR+/+, GITR−/− mice exhibited decreased production of turbid exudate containing a lower number of leukocytes. This was correlated with the reduction of inflammatory markers (including TNF-α, IL-1β, myeloperoxidase, inducible NO synthase, and cyclooxygenase 2) in the pleural exudate and/or in the lung. Moreover, endothelial cells expressed lower levels of adhesion molecules. In lungs of GITR+/+ mice, GITR ligand expression was not modulated during pleurisy, while that of GITR increased, as a consequence of increased infiltration by GITR-expressing cells and of GITR up-regulation in macrophages and endothelial cells. Finally, cotreatment of GITR+/+ mice with carrageenan and Fc-GITR fusion protein decreased the number of inflammatory cells (pleural macrophages and lung neutrophils) as compared with carrageenan treatment alone, confirming that GITR plays a role in the modulation of pleurisy.

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Section: Discussionmentioning

confidence: 95%

“…Following GITR-GITRL interaction, GITRL also delivers signals to APC (13)(14)(15)(16). In vivo studies suggest that GITR triggering exacerbates autoimmune/inflammatory responses and potentiates antiviral and antitumoral immunity (5,17,18).…”

Section: T He Glucocorticoid-induced Tnfr-related Gene (Gitr)mentioning

confidence: 99%

Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

Cuzzocrea

Nocentini

Paola

et al. 2006

The Journal of Immunology

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“…24 The GITRL stimulation induces the expression of proinflammatory cytokines and the phosphorylation of ERK1/2. [27][28][29] The plasmacytoid dendritic cells promote natural killer cell cytotoxic activity and IFN-c production through GITRL-GITR signaling pathway. 30 These studies clearly demonstrate GITRL-mediated signaling as a means of regulating immunological effects of the GITRL-GITR pathway.…”

Section: Discussionmentioning

confidence: 99%

An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand

et al. 2010

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Glucocorticoid-induced tumor-necrosis factor receptor (GITR) and its ligand, GITRL, play significant roles in regulating immune responses. It is clear that human soluble GITRL (hsGITRL) transduces signal activity through multiple oligomerization states. To develop human soluble trimeric GITRL protein as a potential therapeutic target, we explored the link of the isoleucine-zipper (ILZ) motif to the N-terminus of the human soluble GITRL with two leucine sequences. hsGITRL, with the ILZ motif (ILZ-hsGITRL), was firstly expressed in Escherichia coli, which exhibited a predominant trimer when identified by Sephadex G-100 filtration and non-reducing SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The significantly higher biological activity of the ILZ-hsGITRL compared with hsGITRL was confirmed by CD4 1 T proliferation, interferon-c (IFN-c) secretion and binding activity assay. To reveal and compare the underlying mechanisms, the level of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation was examined, indicating that ILZ-hsGITRL induced more persistent and stronger ERK1/2 activation than hsGITRL. In conclusion, the incorporation of an ILZ motif could markedly improve the costimulation of hsGITRL.

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“…Because macrophages and lymphocytes express Cdk4 (37)(38)(39)(40), and because this kinase is up-regulated upon TCR stimulation in T cells or BCR stimulation in B cells (37)(38)(39), the Cdk4R24C mutation would increase the basal and/or stimulated proliferative activity in the autoreactive repertoire. 2) Pancreatic ␤ cells from NOD/Cdk4R24C knockin mice are more susceptible to autoimmune attack.…”

Section: Nod/cdk4r24c Knockin Mice Exhibit Exacerbated Autoimmune Diamentioning

confidence: 99%

Cyclin-Dependent Kinase 4 Hyperactivity Promotes Autoreactivity in the Immune System but Protects Pancreatic β Cell Mass from Autoimmune Destruction in the Nonobese Diabetic Mouse Model

Marzo

Ortega²,

Stratmann

et al. 2008

The Journal of Immunology

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Cyclin-dependent kinase 4 (Cdk4) plays a central role in perinatal pancreatic β cell replication, thus becoming a potential target for therapeutics in autoimmune diabetes. Its hyperactive form, Cdk4R24C, causes β cell hyperplasia without promoting hypoglycemia in a nonautoimmune-prone mouse strain. In this study, we explore whether β cell hyperproliferation induced by the Cdk4R24C mutation balances the autoimmune attack against β cells inherent to the NOD genetic background. To this end, we backcrossed the Cdk4R24C knockin mice, which have the Cdk4 gene replaced by the Cdk4R24C mutated form, onto the NOD genetic background. In this study, we show that NOD/Cdk4R24C knockin mice exhibit exacerbated diabetes and insulitis, and that this exacerbated diabetic phenotype is solely due to the hyperactivity of the NOD/Cdk4R24C immune repertoire. Thus, NOD/Cdk4R24C splenocytes confer exacerbated diabetes when adoptively transferred into NOD/SCID recipients, compared with NOD/wild-type (WT) donor splenocytes. Accordingly, NOD/Cdk4R24C splenocytes show increased basal proliferation and higher activation markers expression compared with NOD/WT splenocytes. However, to eliminate the effect of the Cdk4R24C mutation specifically in the lymphocyte compartment, we introduced this mutation into NOD/SCID mice. NOD/SCID/Cdk4R24C knockin mice develop β cell hyperplasia spontaneously. Furthermore, NOD/SCID/Cdk4R24C knockin females that have been adoptively transferred with NOD/WT splenocytes are more resistant to autoimmunity than NOD/SCID WT female. Thus, the Cdk4R24C mutation opens two avenues in the NOD model: when expressed specifically in β cells, it provides a new potential strategy for β cell regeneration in autoimmune diabetes, but its expression in the immune repertoire exacerbates autoimmunity.

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The soluble glucocorticoid-induced tumor necrosis factor receptor causes cell cycle arrest and apoptosis in murine macrophages

Cited by 20 publications

References 37 publications

Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

Proinflammatory Role of Glucocorticoid-Induced TNF Receptor-Related Gene in Acute Lung Inflammation

An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand

Cyclin-Dependent Kinase 4 Hyperactivity Promotes Autoreactivity in the Immune System but Protects Pancreatic β Cell Mass from Autoimmune Destruction in the Nonobese Diabetic Mouse Model

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