TWEAK Can Induce Pro-Inflammatory Cytokines and Matrix Metalloproteinase-9 in Macrophages

Kim, Se-Hwa; Kang, Younhee; Kim, Wonjung; Woo, Dong-Kyun; Lee, Yoon; Kim, Dong Ik; Park, Yong Bok; Kwon, Byoung S.; Park, Jeong-Euy; Lee, Won‐Ha

doi:10.1253/circj.68.396

Cited by 129 publications

(115 citation statements)

References 13 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…TWEAK treatment stimulates the secretion of IL-8 and GM-CSF from bronchial epithelial cells (14), and of CCL5/RANTES (but not CCL2/MCP-1 or IL-8) from keratinocytes (4). Finally, proinflammatory effects induced by TWEAK were also reported in astrocytes (42) and macrophages (15). However, kidney cells, and specifically mesangial cells, were not previously recognized as being TWEAK responsive.…”

Section: Discussionmentioning

confidence: 95%

“…In HUVECs, TWEAK (alone or in combination with other growth factors) enhances cell proliferation, migration, and resistance to apoptosis, and induces ICAM-1, Eselectin, CCL2/MCP-1, and IL-8 expression (9 -12). Proinflammatory cytokine secretion has also been recently described following TWEAK stimulation of synoviocytes, fibroblasts (13), bronchial epithelial cells (14), and macrophages (15).…”

mentioning

confidence: 94%

See 1 more Smart Citation

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

The Journal of Immunology

152

187

View full text Add to dashboard Cite

TNF-like weak inducer of apoptosis, or TWEAK, is a relatively new member of the TNF-ligand superfamily. Ligation of the TWEAK receptor Fn14 by TWEAK has proinflammatory effects on fibroblasts, synoviocytes, and endothelial cells. Several of the TWEAK-inducible cytokines are important in the pathogenesis of kidney diseases; however, whether TWEAK can induce a proinflammatory effect on kidney cells is not known. We found that murine mesangial cells express cell surface TWEAK receptor. TWEAK stimulation of mesangial cells led to a dose-dependent increase in CCL2/MCP-1, CCL5/RANTES, CXCL10/IFN-γ-induced protein 10 kDa, and CXCL1/KC. The induced levels of chemokines were comparable to those found following mesangial cell exposure to potent proinflammatory stimuli such as TNF-α + IL-1β. CXCL11/interferon-inducible T cell α chemoattractant, CXCR5, mucosal addressin cell adhesion molecule-1, and VCAM-1 were up-regulated by TWEAK as well. TWEAK stimulation of mesangial cells resulted in an increase in phosphorylated Iκ-B, while pretreatment with an Iκ-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-κB signaling pathway in TWEAK-induced chemokine secretion. Importantly, the Fn14-mediated proinflammatory effects of TWEAK on kidney cells were confirmed using mesangial cells derived from Fn14-deficient mice and by injection in vivo of TWEAK into wild-type vs Fn14-deficient mice. Finally, TWEAK-induced chemokine secretion was prevented by treatment with novel murine anti-TWEAK Abs. We conclude that TWEAK induces mesangial cells to secrete proinflammatory chemokines, suggesting a prominent role for TWEAK in the pathogenesis of renal injury. Our results support Ab inhibition of TWEAK as a potential new approach for the treatment of chemokine-dependent inflammatory kidney diseases.

show abstract

Section: Discussionmentioning

confidence: 95%

mentioning

confidence: 94%

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Campbell

Burkly

Gao

et al. 2006

The Journal of Immunology

152

187

View full text Add to dashboard Cite

show abstract

“…Stimulation of human umbilical vein endothelial cells with TWEAK also induces the secretion of proinflammatory cytokines and chemokines such as IL-8 and monocyte chemoattractant protein 1 (27), increasing the inflammatory response. In addition, TWEAK augments vascular smooth muscle cell proliferation (13) and induces metalloproteinase activity (16), favoring atherosclerotic plaque destabilization. Finally, TWEAK and Fn14 are expressed in human carotid atherosclerotic plaques (43).…”

Section: Discussionmentioning

confidence: 99%

Soluble TWEAK Plasma Levels as a Novel Biomarker of Endothelial Function in Patients with Chronic Kidney Disease

Yılmaz¹,

Carrero²,

Ortíz³

et al. 2009

Clinical Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Background and objectives: Recently, we showed that soluble TNF-like weak inducer of apoptosis (sTWEAK) plasma levels are diminished in hemodialysis patients and had additive effects with IL-6 on survival. Because sTWEAK plasma level has been associated with the presence of chronic kidney disease (CKD) and cardiovascular disease, we hypothesized that in patients with CKD, sTWEAK levels may relate to the increased prevalence of endothelial dysfunction that usually accompanies the decline of estimated GFR (eGFR).Design, setting, participants, & measurements: We studied 295 patients with different stages of nondiabetic CKD (52% male; age 47 ؎ 12 yr), testing the association between sTWEAK plasma levels and CKD stage and the relationship between flow-mediated dilation (FMD) and sTWEAK concentrations. Fifty-five healthy volunteers (51% male; age 47 ؎ 11 yr) served as matched control subjects.Results: A gradual decrease in FMD was observed as eGFR decreased. Compared with healthy control subjects, sTWEAK plasma levels were diminished in all stages of CKD and correlated strongly with eGFR. FMD levels were associated with sTWEAK concentrations in univariate analysis. This association persisted after multivariate adjustment for eGFR levels, high-sensitivity C-reactive protein, diastolic BP, and sTWEAK, all of which were found to be significant and independent contributors to FMD.Conclusions: A decline in eGFR is accompanied by gradual reductions in sTWEAK plasma levels. Because sTWEAK strongly and independently correlated with FMD, our study suggests novel links between sTWEAK and endothelial dysfunction in patients with CKD.

show abstract

“…Because TWEAK induces activation of the NF-kB pathway when added to various cell types Donohue et al, 2003;Kim et al, 2004), and when injected directly into the brain (Polavarapu et al, 2005), we investigated the effect of endogenous TWEAK on cerebral ischemia-induced NF-kB pathway activation. The IkB kinase (IKK) complex is composed of two catalytic subunits (a and b) and Figure 3 Genetic deficiency of Fn14 improves motor activity, decreases cerebral edema, and protects the integrity of the neurovascular unit after MCAO.…”

Section: Tweak Contributes To Cerebral Ischemia-induced Nuclear Factomentioning

confidence: 99%

TWEAK—Fn14 Pathway Inhibition Protects the Integrity of the Neurovascular Unit during Cerebral Ischemia

Zhang

Winkles

Góngora

et al. 2006

J Cereb Blood Flow Metab

104

View full text Add to dashboard Cite

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit (NVU) during cerebral ischemia, TWEAK activity was inhibited in wild-type mice with a soluble Fn14-Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion (MCAO). Administration of Fn14-Fc decoy resulted in faster recovery of motor function and a 66.4%610% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1%613.1% decrease when animals were treated 1 h later (n = 4, P < 0.05). Genetic deficiency of Fn14 resulted in a 60%612.8% decrease in the volume of the ischemic lesion (n = 6, P < 0.05), and a 87%622% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult (n = 6, P < 0.005). Compared with control animals, treatment with Fn14-Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor-jB pathway activation, matrix metalloproteinase-9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.

show abstract

TWEAK Can Induce Pro-Inflammatory Cytokines and Matrix Metalloproteinase-9 in Macrophages

Cited by 129 publications

References 13 publications

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Proinflammatory Effects of Tweak/Fn14 Interactions in Glomerular Mesangial Cells

Soluble TWEAK Plasma Levels as a Novel Biomarker of Endothelial Function in Patients with Chronic Kidney Disease

TWEAK—Fn14 Pathway Inhibition Protects the Integrity of the Neurovascular Unit during Cerebral Ischemia

Contact Info

Product

Resources

About