TNF-like weak inducer of apoptosis (TWEAK) induces inflammatory and proliferative effects in human kidney cells.
Members of the TNF-ligand and receptor superfamilies are important in the pathogenesis of lupus nephritis, a major cause of mortality and morbidity in SLE. TWEAK, a member of the TNF-ligand superfamily, is markedly increased in urine from patients with active lupus nephritis, and urinary TWEAK levels significantly correlate with renal disease activity. To support a possible role of TWEAK in the pathogenesis of lupus nephritis and other inflammatory nephritides, we examined the effects of TWEAK in human kidney mesangial cells, podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. We found that TWEAK induces human kidney cells to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1alpha, ICAM-1, and VCAM-1. Cytokine production is mediated through NF-kappaB activation, and is inhibited by anti-TWEAK monoclonal antibodies. TWEAK stimulated chemokines induced migration of human PBMC, particularly monocytes/macrophages. Furthermore, we found that TWEAK promotes kidney infiltration of inflammatory cells, and stimulates proliferation of kidney cells in vitro and in vivo. Thus, TWEAK may play an important pathogenic role in the development of glomerulonephritis by promoting a local inflammatory environment and inducing kidney cell proliferation. Blocking TWEAK/Fn14 interactions may be a promising therapeutic target in immune-mediated renal diseases.
Gao
Hua-Xin
HX
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Campbell
Sean R
SR
Burkly
Linda C
LC
Jakubowski
Aniela
A
Jarchum
Irene
I
Banas
Bernhard
B
Saleem
Moin A
MA
Mathieson
Peter W
PW
Berman
Joan W
JW
Michaelson
Jennifer S
JS
Putterman
Chaim
C
D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D005921:Glomerulonephritis / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007668:Kidney / Q000166:cytology* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000074050:TWEAK Receptor
D016207:Cytokines; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse