# IL-35 inhibits gut microbiota-produced uremic toxin-accelerated endothelial cell activation

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2021 · $648,249

## Abstract

IL-35 inhibits gut microbiota-produced uremic toxin-accelerated endothelial cell
activation
Chronic kidney disease (CKD) affects 15% of the adult population worldwide. CKD promotes
cardiovascular morbidity and mortality. Increased endothelial cell (EC) activation/dysfunction
and vascular inflammation play a critical role the development of CKD-accelerated
cardiovascular disease (CVD), which begins in the early stages of CKD. New therapies are
urgently needed to inhibit EC activation/dysfunction accelerated by CKD. EC dysfunction is
associated with reduced nitric oxide (NO) production whereas our new JBC paper showed EC
activation features include: 1) increased secretion of cytokines and chemokines; 2) upregulation
of EC adhesion molecules; 3) upregulation of additional DAMP receptors; and 4) upregulation of
T cell co-stimulation/co-inhibition receptors. Novel strategies targeted at reducing EC
activation/dysfunction and vascular inflammation may provide effective treatment in the early
stages of CKD. Trimethylamine-N-Oxide (TMAO) is a gut microbiota generated, choline-derived
metabolite. TMAO is a newly identified as a uremic toxin, which is strongly elevated in CKD and
associated with atherosclerotic CVDs. TMAO induces EC dysfunction and increased vascular
inflammation via binding to G-protein coupled receptor, thereby activating mitogen‐activated
protein kinase and NF‐κB, and increasing circulating cytokines. We and others reported that
interleukin-35 (IL-35) is a new and powerful anti-inflammatory cytokine that inhibits various
inflammation. Plasma IL-35 levels are increased in CKD patients. Therefore, the central
hypothesis of this proposal is that IL-35 suppresses uremic toxin TMAO-induced EC
activation/dysfunction and CKD-accelerated vascular inflammation. Therefore, we will examine
this hypothesis via following three aims: 1) To determine expression and suppressive function
of IL-35/IL-35R subunits in TMAO-induced human aortic ECs (HAECs) and mouse aortic ECs
(MRECs) from CKD mice; 2) To determine the molecular mechanisms, by which IL-35 inhibits
EC activation via inhibiting mitochondrial reactive oxygen species (mtROS) generation,
suppressing caspase-1(casp1) canonical/casp11 non-canonical inflammasome signaling, and
inhibiting histone 3 lysine 14 acetylation (H3K14ac) induced EC activation gene expression; and
3) To determine the suppressing roles of two IL-35 subunits (p35, and EBI3) and an IL-35
receptor (IL-35R) subunit (IL12Rβ2) in CKD mouse model. The aim 3 will be explored through
the use of a novel IL-35 therapy (gain of function) in CKD mouse model, and four loss of
function CKD models including p35-/- CKD mice, EBI-3-/- CKD mice, global IL-12Rβ2-/- CKD
mice and EC-specific IL12Rb2-/- CKD mice to determine the suppressive roles of IL-35
signaling in EC dysfunction and vascular inflammation in CKD. The significance of this
proposal is that the success of these studies should have a major impact in the field, and
provide novel mech...

## Key facts

- **NIH application ID:** 10128493
- **Project number:** 5R01HL147565-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Xiaofeng Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $648,249
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128493

## Citation

> US National Institutes of Health, RePORTER application 10128493, IL-35 inhibits gut microbiota-produced uremic toxin-accelerated endothelial cell activation (5R01HL147565-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10128493. Licensed CC0.

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