Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.
OBJECTIVE
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice.


RESULTS
ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti-TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF-kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion.


CONCLUSIONS
Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with hyperlipidemia.
Vascular Research Laboratory, Fundación Jiménez Díaz, Madrid, Spain.
Begoña
B
Muñoz-García
Juan Antonio
JA
Moreno
Oscar
O
López-Franco
Ana Belén
AB
Sanz
José Luis
JL
Martín-Ventura
Julia
J
Blanco
Aniela
A
Jakubowski
Linda C
LC
Burkly
Alberto
A
Ortiz
Jesús
J
Egido
Luis Miguel
LM
Blanco-Colio
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D001808:Blood Vessels / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D000074049:Cytokine TWEAK; D016207:Cytokines / Q000235:genetics; D004036:Diet, Atherogenic; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006949:Hyperlipidemias / Q000473:pathology* / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D000074049:Cytokine TWEAK; D016207:Cytokines; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D011994:Recombinant Proteins; C109743:TNFSF12 protein, human; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; C099252:oxidized low density lipoprotein