Abstract
OBJECTIVE - : Interleukin-19 (IL-19) is a putative Th2, anti-inflammatory interleukin. Its expression and potential role in atherogenesis are unknown. IL-19 is not detected in normal artery and is expressed to a greater degree in plaque from symptomatic versus asymptomatic patients, suggesting a compensatory counter-regulatory function. We tested whether IL-19 could reduce atherosclerosis in susceptible mice and identified plausible mechanisms. APPROACH AND RESULTS - : LDLR mice fed an atherogenic diet and injected with either 1.0 or 10.0 ng/g per day recombinant mouse IL-19 had significantly less plaque area in the aortic arch compared with controls (P<0.0001). Weight gain, cholesterol, and triglyceride levels were not significantly different. Gene expression in splenocytes from IL-19-treated mice demonstrated immune cell Th2 polarization, with decreased expression of T-bet, interferon-γ, interleukin-1β, and interleukin-12β and increased expression of GATA3 and FoxP3 mRNA. A greater percentage of lymphocytes were Th2 polarized in IL-19-treated mice. Cellular characterization of plaque by immunohistochemistry demonstrated that IL-19-treated mice have significantly less macrophage infiltrate compared with controls (P<0.001). Intravital microscopy revealed significantly less leukocyte adhesion in wild-type mice injected with IL-19 and fed an atherogenic diet compared with controls. Treatment of cultured endothelial cells, vascular smooth muscle cells, and bone marrow-derived macrophages with IL-19 resulted in a significant decrease in chemokine mRNA and mRNA stability protein human antigen R. CONCLUSIONS - : These data suggest that IL-19 is a potent inhibitor of experimental atherosclerosis, with diverse mechanisms including immune cell polarization, decrease in macrophage adhesion, and decrease in gene expression. This may identify IL-19 as a novel therapeutic to limit vascular inflammation.
Original language | English |
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Pages (from-to) | 2316-2324 |
Number of pages | 9 |
Journal | Arteriosclerosis, Thrombosis, and Vascular Biology |
Volume | 33 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2013 |
Keywords
- Aged
- Animals
- Aorta/drug effects
- Aortic Diseases/genetics
- Apolipoproteins E/deficiency
- Atherosclerosis/genetics
- Biomarkers/blood
- Carotid Artery Diseases/immunology
- Cells, Cultured
- Cholesterol/blood
- Disease Models, Animal
- Endothelial Cells/drug effects
- Female
- Gene Expression Regulation/drug effects
- Humans
- Inflammation Mediators/metabolism
- Interleukin-10/metabolism
- Interleukins/metabolism
- Macrophages/drug effects
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Myocytes, Smooth Muscle/drug effects
- Plaque, Atherosclerotic
- Receptors, LDL/deficiency
- Recombinant Proteins/pharmacology
- Spleen/drug effects
- Th2 Cells/drug effects
- Time Factors
- Triglycerides/blood