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Analyzing the Effects of Stromal Cells on the Recruitment of Leukocytes from Flow
Published on: January 7, 2015
NF-kappaB is required for TNF-alpha-directed smooth muscle cell migration.
Z Wang1, M R Castresana, W H Newman
1Division of Basic Medical Science, Mercer University School of Medicine, Macon, GA 31207, USA. wang_z@mercer.edu
FEBS Letters
|December 1, 2001
Summary
Tumor necrosis factor-alpha (TNF-alpha) triggers vascular smooth muscle cell (VSMC) migration via nuclear factor-kappaB (NF-kappaB) activation. This process involves interleukin-6 and -8 (IL-6/IL-8) acting in an autocrine manner.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cellular Signaling
Background:
- Vascular smooth muscle cell (VSMC) migration is central to vascular stenotic lesion development.
- Tumor necrosis factor-alpha (TNF-alpha) is implicated in atherosclerosis and post-angioplasty restenosis.
- The role of nuclear factor-kappaB (NF-kappaB) in TNF-alpha-induced VSMC migration is not fully understood.
Purpose of the Study:
- To investigate the involvement of NF-kappaB in TNF-alpha-mediated human VSMC migration.
- To elucidate the downstream signaling pathways, including cytokine production, regulated by NF-kappaB in this context.
Main Methods:
- Adenoviral expression of a dominant-negative inhibitor of NF-kappaB (IkappaB-alphaM) in human VSMC.
- Assessment of IkappaB-alpha degradation and NF-kappaB activation.
- Measurement of VSMC migration, and release of interleukin-6 (IL-6) and interleukin-8 (IL-8).
- Inhibition of IL-6/IL-8 using neutralizing antibodies and stimulation with recombinant cytokines.
Main Results:
- IkappaB-alphaM expression inhibited TNF-alpha-induced IkappaB-alpha degradation and NF-kappaB activation.
- Suppression of NF-kappaB activation attenuated TNF-alpha-induced VSMC migration.
- TNF-alpha stimulation led to increased IL-6 and IL-8 release, which was reduced by IkappaB-alphaM.
- Neutralization of IL-6/IL-8 decreased TNF-alpha-induced migration, while their addition enhanced migration.
Conclusions:
- TNF-alpha-induced VSMC migration is dependent on NF-kappaB activation.
- The pro-migratory effect of TNF-alpha is mediated, in part, by the autocrine action of induced IL-6 and IL-8.
- This study provides evidence for a signaling cascade involving TNF-alpha, NF-kappaB, and IL-6/IL-8 in VSMC migration.
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