Related Experiment Video
Updated: May 4, 2026
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Adiponectin inhibits tumor necrosis factor-α-induced vascular inflammatory response via caveolin-mediated ceramidase
Yajing Wang1, Xiaoliang Wang, Wayne Bond Lau
1From the Department of Emergency Medicine (Y.W., X.W., W.B.L., Y.Y., J.-J.L., X.-L.M.) and Department of Pathology (D.B.), Thomas Jefferson University, Philadelphia, PA; and Department of Physiology, Cardiovascular Research Center (R.S., K.P.) and Center for Translational Medicine (E.G., W.K.), Temple University, Philadelphia, PA.
Rationale:
Anti-inflammatory and vascular protective actions of adiponectin are well recognized. However, many fundamental questions remain unanswered.
Objective:
The current study attempted to identify the adiponectin receptor subtype responsible for adiponectin's vascular protective action and investigate the role of ceramidase activation in adiponectin anti-inflammatory signaling.
Methods And Results:
Adiponectin significantly reduced tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and attenuated TNFα-induced oxidative/nitrative stress in human umbilical vein endothelial cells. These anti-inflammatory actions were virtually abolished by adiponectin receptor 1 (AdipoR1-), but not AdipoR2-, knockdown (KD). Treatment with adiponectin significantly increased neutral ceramidase (nCDase) activity (3.7-fold; P<0.01). AdipoR1-KD markedly reduced globular adiponectin-induced nCDase activation, whereas AdipoR2-KD only slightly reduced. More importantly, small interfering RNA-mediated nCDase-KD markedly blocked the effect of adiponectin on TNFα-induced intercellular adhesion molecule-1 expression. AMP-activated protein kinase-KD failed to block adiponectin-induced nCDase activation and modestly inhibited adiponectin anti-inflammatory effect. In contrast, in caveolin-1 KD (Cav1-KD) cells, >87% of adiponectin-induced nCDase activation was lost. Whereas adiponectin treatment failed to inhibit TNFα-induced intercellular adhesion molecule-1 expression, treatment with sphingosine-1-phosphate or SEW (sphingosine-1-phosphate receptor agonist) remained effective in Cav1-KD cells. AdipoR1 and Cav1 colocalized and coprecipitated in human umbilical vein endothelial cells. Adiponectin treatment did not affect this interaction. There is weak basal Cav1/nCDase interaction, which significantly increased after adiponectin treatment. Knockout of AdipoR1 or Cav1 abolished the inhibitory effect of adiponectin on leukocyte rolling and adhesion in vivo.
Conclusions:
These results demonstrate for the first time that adiponectin inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1-dependent fashion.
Insights
Adiponectin reduces inflammation by activating ceramidase through AdipoR1 and caveolin-1. This pathway is crucial for adiponectin's vascular protective effects, highlighting a novel mechanism in endothelial cells.
Area of Science:
- Endocrinology
- Molecular Biology
- Vascular Biology
Background:
- Adiponectin is known for its anti-inflammatory and vascular protective effects.
- However, the specific receptor and signaling pathways involved remain incompletely understood.
Purpose of the Study:
- To identify the adiponectin receptor subtype mediating vascular protection.
- To investigate the role of ceramidase activation in adiponectin's anti-inflammatory signaling.
Main Methods:
- Utilized human umbilical vein endothelial cells with adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) knockdown.
- Assessed tumor necrosis factor (TNF)α-induced intercellular adhesion molecule-1 expression and oxidative stress.
- Measured neutral ceramidase (nCDase) activity and employed small interfering RNA (siRNA) for nCDase and caveolin-1 (Cav1) knockdown.
- Investigated protein interactions using co-precipitation and evaluated in vivo leukocyte-endothelial cell interactions.
Main Results:
- Adiponectin reduced TNFα-induced inflammation and oxidative stress, an effect dependent on AdipoR1.
- Adiponectin significantly increased nCDase activity, mediated primarily by AdipoR1 and caveolin-1.
- Knockdown of nCDase or Cav1 abolished adiponectin's anti-inflammatory effects.
- AdipoR1 and Cav1 colocalized and their interaction with nCDase increased upon adiponectin treatment.
- In vivo, AdipoR1 or Cav1 knockout abrogated adiponectin's inhibition of leukocyte adhesion.
Conclusions:
- Adiponectin inhibits TNFα-induced inflammation via AdipoR1-dependent recruitment and activation of ceramidase, mediated by caveolin-1.
- This study elucidates a novel molecular mechanism for adiponectin's vascular protective actions.
More Related Videos
07:15Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
Published on: August 23, 2024
08:41Assessment of Vascular Tone Responsiveness using Isolated Mesenteric Arteries with a Focus on Modulation by Perivascular Adipose Tissues
Published on: June 3, 2019
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:17Intracellular Signaling Affects Focal Adhesions
Some...
01:16TGF - β Signaling Pathway
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
02:26NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The...
01:35Cancer Cell Migration through Invadopodia