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Attenuation of experimental atherosclerosis by interleukin-19.

ABSTRACT: 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.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-?, interleukin-1?, and interleukin-12? 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.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.

SUBMITTER: Ellison S

PROVIDER: S-EPMC3950941 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Attenuation of experimental atherosclerosis by interleukin-19.

Ellison Stephen S Gabunia Khatuna K Kelemen Sheri E SE England Ross N RN Scalia Rosario R Richards James M JM Orr A Wayne AW Traylor James G JG Rogers Thomas T Cornwell William W Berglund Lisa M LM Goncalves Isabel I Gomez Maria F MF Autieri Michael V MV

Arteriosclerosis, thrombosis, and vascular biology 20130815 10

<h4>Objective</h4>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.<h4>Approach and results</h4>LDLR(-/-) mice fed ...[more]

PMID: 23950143

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Project description:BackgroundIntravenous immunoglobulin (IVIg) has been used to treat a variety of autoimmune disorders including multiple sclerosis (MS); however its mechanism of action remains elusive. Recent work has shown that interleukin-11 (IL-11) mRNAs are upregulated by IVIg in MS patient T cells. Both IVIg and IL-11 have been shown to ameliorate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The objective of this study was to determine whether the protective effects of IVIg in EAE occur through an IL-11 and IL-11 receptor (IL-11R)-dependent mechanism.MethodsWe measured IL-11 in the circulation of mice and IL-11 mRNA expression in various organs after IVIg treatment. We then followed with EAE studies to test the efficacy of IVIg in wild-type (WT) mice and in mice deficient for the IL-11 receptor (IL-11Rα-/-). Furthermore, we evaluated myelin-specific Th1 and Th17 responses and assessed spinal cord inflammation and demyelination in WT and IL-11Rα-/- mice, with and without IVIg treatment. We also examined the direct effects of mouse recombinant IL-11 on the production of IL-17 by lymph node mononuclear cells.ResultsIVIg treatment induced a dramatic surge (>1000-fold increase) in the levels of IL-11 in the circulation and a prominent increase of IL-11 mRNA expression in the liver. Furthermore, we found that IL-11Rα-/- mice, unlike WT mice, although initially protected, were resistant to full protection by IVIg during EAE and developed disease with a similar incidence and severity as control-treated IL-11Rα-/- mice, despite initially showing protection. We observed that Th17 cytokine production by myelin-reactive T cells in the draining lymph nodes was unaffected by IVIg in IL-11Rα-/- mice, yet was downregulated in WT mice. Finally, IL-11 was shown to directly inhibit IL-17 production of lymph node cells in culture.ConclusionThese results implicate IL-11 as an important immune effector of IVIg in the prevention of Th17-mediated autoimmune inflammation during EAE.

Project description:Background: Arteriosclerosis (AS) involves arterial inflammation. Using macrophage-based drug delivery system, we aim to enhance local drug concentration, especially for short-lived anti-inflammatory molecules like interleukin-10. Our study intervenes in plaque progression by boosting IL-10 expression in macrophages lentiviral transfection and introducing these anti-inflammatory cells into Apoe-/- mice. Methods: We engineered RAW264.7 cells to overexpress IL-10 (referred to as IL-10M) using lentivirus vectors. Subsequent in vitro experiments were conducted to validate the effects and cellular functions of IL-10M. Fluorescence imaging allowed us to track the localization of IL-10M at atherosclerotic plaque sites after intravenous (IV) injection in Apoe-/- mice. We administered periodic injections of IL-10M at different stages of plaque progression in AS mice to assess its therapeutic impact on plaque advancement. Following the intervention, we collected samples from major organs and serum to evaluate the safety of IL-10M treatment. Results: Our engineered IL-10M exhibits robust IL-10 secretion, maintaining macrophage phagocytic function, and showing a tendency toward an M2 phenotype when exposed to inflammatory stimuli. Upon intravenous IL-10M administration, fluorescence imaging highlights precise plaque localization in both global and cross-sectional aortic regions. Regardless of whether intervention is initiated early or late in plaque progression, we observe significant reductions in plaque area and necrotic core. Importantly, IL-10M intervention does not impact the histological characteristics of the heart, liver, spleen, lungs, and kidneys, nor does it influence systemic inflammation levels. Conclusion: Our team has devised a novel anti-inflammatory protein delivery system utilizing modified macrophages, which exhibit a remarkable ability to target atherosclerotic plaques, resulting in the reduction of both plaque area and necrotic core. This innovative approach demonstrates favorable safety profiles and holds significant potential as a therapeutic strategy for managing atherosclerosis.

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Attenuation of experimental atherosclerosis by interleukin-19.

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Attenuation of experimental atherosclerosis by interleukin-19.

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