Interleukin-35 Ameliorates Obesity-Associated Impairment of Endothelium-Dependent Vasodilation via the STAT3-MAPK/ERK-eNOS Signaling Axis.
- 1Department of Cardiology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
- 2Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
Abstract
Background
Obesity impairs endothelial nitric oxide synthase (eNOS)-nitric oxide (NO) signaling, triggering chronic inflammation, endothelial dysfunction and defective vasodilation, which drives cardiometabolic diseases. Existing metabolic therapies provide only indirect vascular protection and fail to resolve residual inflammatory-mediated cardiovascular risk. As an anti-inflammatory interleukin 12 (IL-12) family cytokine, interleukin 35 (IL-35) is suppressed in obesity and exerts vascular protective effects under inflammatory conditions, yet its function and underlying mechanisms in obesity‑related endothelial vasodilator dysfunction remain undefined.Materials and methods
An obese mouse model was established by 8-week high-fat diet (HFD) feeding, followed by 4-week intraperitoneal administration of recombinant mouse IL-35. Aortic-ring assays evaluated vasodilatory function. Palmitic acid (PA)-treated human umbilical vein endothelial cells (HUVECs), recapitulate lipotoxic endothelial injury, were treated with recombinant human IL-35. Western blotting, immunofluorescence, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA) detection and immunoprecipitation-mass spectrometry (IP-MS) were applied to detect IL-35-subunit (Epstein-Barr virus-induced gene 3 [EBI3] and interleukin-12 subunit alpha [IL-12A]) levels, eNOS Ser1177 phosphorylation, phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling molecules (cellular rapidly accelerated fibrosarcoma [cRAF], mitogen-activated protein kinase kinase [MEK], and ERK) and signal transducer and activator of transcription 3 (STAT3) activation, NO production, and eNOS-binding partners. Rescue assays were performed using Raf or ERK specific inhibitors and STAT3 small interfering RNA (siRNA).Results
HFD mice displayed reduced aortic endothelial EBI3 expression, impaired endothelium-dependent vasorelaxation, decreased eNOS Ser1177 phosphorylation and lowered NO production; all these phenotypes were rescued by exogenous IL-35. IP-MS and immunoblotting demonstrated that IL-35 strengthened eNOS-ERK1 interaction and restored PA-repressed phosphorylation of cRAF, MEK, ERK and eNOS Ser1177, which were abrogated by Raf or ERK blockade. Furthermore, IL-35 recovered STAT3 phosphorylation suppressed by PA, while STAT3 knockdown blunted IL-35-driven MAPK/ERK activation, eNOS phosphorylation and subsequent NO production.Conclusion
IL-35 alleviates obesity-induced impairment of endothelium-dependent vasodilation via the STAT3-MAPK/ERK-eNOS axis, which elevates eNOS Ser1177 phosphorylation and NO synthesis. This work supports IL-35 as a prospective therapeutic candidate for obesity-associated vascular complications.
Related
- Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in SAE Mice by Relieving STING‐Associated Inhibition of PKM2 Activity
- Astragaloside IV ameliorates cognitive impairment after traumatic brain injury with involvement of NMDAR-related signaling
- Ishige foliacea Water Extract (KDC22-01) Attenuates Tau Hyperphosphorylation and Ameliorates Scopolamine-Induced Memory Impairment in Mice
- Plant‐Derived Senolytic Ingredient, Camellia sinensis Root Extract, Ameliorates Skin Aging‐Associated Phenotypes
- Single-cell RNA Sequencing Analysis Reveals That Targeting PLG–PLGRKT Signaling-mediated Pro-fibrotic Scar-associated Macrophages Ameliorates Liver Fibrosis in Biliary Atresia
BibTeX
@article{li2026interleukin35,
title = {{Interleukin-35 Ameliorates Obesity-Associated Impairment of Endothelium-Dependent Vasodilation via the STAT3-MAPK/ERK-eNOS Signaling Axis.}},
author = {Kai Li and Jie Feng and Ren Gong and Yunman Liu and Yanqing Wu},
journal = {Immunity, inflammation and disease},
year = {2026},
month = oct,
doi = {10.1002/iid3.70564},
url = {https://europepmc.org/article/MED/42910842},
note = {CC BY},
}
RIS
TY - JOUR
TI - Interleukin-35 Ameliorates Obesity-Associated Impairment of Endothelium-Dependent Vasodilation via the STAT3-MAPK/ERK-eNOS Signaling Axis.
AU - Kai Li
AU - Jie Feng
AU - Ren Gong
AU - Yunman Liu
AU - Yanqing Wu
PY - 2026
DA - 2026/10/01
JO - Immunity, inflammation and disease
DO - 10.1002/iid3.70564
UR - https://europepmc.org/article/MED/42910842
AB - Background Obesity impairs endothelial nitric oxide synthase (eNOS)-nitric oxide (NO) signaling, triggering chronic inflammation, endothelial dysfunction and defective vasodilation, which drives cardiometabolic diseases. Existing metabolic therapies provide only indirect vascular protection and fail to resolve residual inflammatory-mediated cardiovascular risk. As an anti-inflammatory interleukin 12 (IL-12) family cytokine, interleukin 35 (IL-35) is suppressed in obesity and exerts vascular protective effects under inflammatory conditions, yet its function and underlying mechanisms in obesity‑related endothelial vasodilator dysfunction remain undefined.Materials and methods An obese mouse model was established by 8-week high-fat diet (HFD) feeding, followed by 4-week intraperitoneal administration of recombinant mouse IL-35. Aortic-ring assays evaluated vasodilatory function. Palmitic acid (PA)-treated human umbilical vein endothelial cells (HUVECs), recapitulate lipotoxic endothelial injury, were treated with recombinant human IL-35. Western blotting, immunofluorescence, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA) detection and immunoprecipitation-mass spectrometry (IP-MS) were applied to detect IL-35-subunit (Epstein-Barr virus-induced gene 3 [EBI3] and interleukin-12 subunit alpha [IL-12A]) levels, eNOS Ser1177 phosphorylation, phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling molecules (cellular rapidly accelerated fibrosarcoma [cRAF], mitogen-activated protein kinase kinase [MEK], and ERK) and signal transducer and activator of transcription 3 (STAT3) activation, NO production, and eNOS-binding partners. Rescue assays were performed using Raf or ERK specific inhibitors and STAT3 small interfering RNA (siRNA).Results HFD mice displayed reduced aortic endothelial EBI3 expression, impaired endothelium-dependent vasorelaxation, decreased eNOS Ser1177 phosphorylation and lowered NO production; all these phenotypes were rescued by exogenous IL-35. IP-MS and immunoblotting demonstrated that IL-35 strengthened eNOS-ERK1 interaction and restored PA-repressed phosphorylation of cRAF, MEK, ERK and eNOS Ser1177, which were abrogated by Raf or ERK blockade. Furthermore, IL-35 recovered STAT3 phosphorylation suppressed by PA, while STAT3 knockdown blunted IL-35-driven MAPK/ERK activation, eNOS phosphorylation and subsequent NO production.Conclusion IL-35 alleviates obesity-induced impairment of endothelium-dependent vasodilation via the STAT3-MAPK/ERK-eNOS axis, which elevates eNOS Ser1177 phosphorylation and NO synthesis. This work supports IL-35 as a prospective therapeutic candidate for obesity-associated vascular complications.
SN - 2050-4527
ER -