Interleukin-32α Inhibits Endothelial Inflammation, Vascular Smooth Muscle Cell Activation, and Atherosclerosis by Upregulating Timp3 and Reck through suppressing microRNA-205 Biogenesis

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Abstract

Interleukin-32 (IL-32) is a multifaceted cytokine that promotes inflammation and regulates vascular endothelial cell behavior. Although some IL-32 isoforms have been reported to contribute to vascular inflammation and atherosclerosis, the functional role of IL-32α in vascular inflammation and atherogenesis has not been studied.

Methods: IL-32α function was assessed in cells with transient IL-32α overexpression or treated with recombinant human IL-32α by western blotting and mRNA expression analysis. Vascular smooth muscle cell (VSMC) proliferation and migration was examined by BrdU incorporation and wound healing assays, respectively. In addition, the participation of IL-32α on vascular inflammation, arterial wall thickening, and atherosclerosis in vivo was monitored in human IL-32α transgenic (hIL-32α-Tg) mice with or without ApoE knockout (ApoE ^-/- /hIL-32α-Tg).

Results: Our analyses showed that IL-32α suppresses genes involved in the inflammatory and immune responses and cell proliferation, and by limiting matrix metalloproteinase (MMP) function. In vivo, administration of hIL-32α inhibited vascular inflammation and atherosclerosis in hIL-32α-Tg and ApoE ^-/- /hIL-32α-Tg mice. Subsequent microarray and in silico analysis also revealed a marked decreased in inflammatory gene expression in hIL-32α-Tg mice. Collectively, our studies demonstrated that IL-32α upregulates the atheroprotective genes Timp3 and Reck by downregulating microRNA-205 through regulation of the Rprd2-Dgcr8/Ddx5-Dicer1 biogenesis pathway.

Conclusion: Our findings provide the first direct evidence that IL-32α is an anti-inflammatory and anti-atherogenic cytokine that may be useful as a diagnostic and therapeutic protein in atherosclerosis.

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The RNA-binding Protein KSRP Promotes the Biogenesis of a Subset of miRNAs

Michele Trabucchi, Paola Briata, MaríaFlor García-Mayoral … (2009)

Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing translation and/or stability of target mRNAs1, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer2-4. However, the regulatory mechanisms by which primary miRNAs (pri-miRNAs) are processed first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs by the multiprotein Drosha and Dicer complexes5-8, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP) interacts with single strand AU-rich elements (ARE)-containing mRNAs and is a key mediator of mRNA decay9,10. Here, we show that KSRP also serves as a component of both Drosha and Dicer complexes and regulates the biogenesis of a subset of miRNAs. KSRP binds with high affinity to the terminal loop (TL) of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affects specific biological programs, including proliferation, apoptosis and differentiation. These findings reveal an unexpected mechanism that links KSRP to the machinery regulating maturation of a cohort of miRNAs, that, in addition to its role in promoting mRNA decay, independently serves to integrate specific regulatory programs of protein expression.

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Endothelial cell functions.

Carine Michiels (2003)

Endothelial cells play a wide variety of critical roles in the control of vascular function. Indeed, since the early 1980s, the accumulating knowledge of the endothelial cell structure as well as of the functional properties of the endothelial cells shifted their role from a passive membrane or barrier to a complex tissue with complex functions adaptable to needs specific in time and location. Hence, it participates to all aspects of the vascular homeostasis but also to physiological or pathological processes like thrombosis, inflammation, or vascular wall remodeling. Some of the most important endothelial functions will be described in the following review and more specifically, their role in blood vessel formation, in coagulation and fibribolysis, in the regulation of vascular tone as well as their participation in inflammatory reactions and in tumor neoangiogenesis. Copyright 2003 Wiley-Liss, Inc.

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Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets

Dipak Ramji, Thomas S. Davies (2015)

Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions.

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Author and article information

Journal

Journal ID (nlm-ta): Theranostics

Journal ID (iso-abbrev): Theranostics

Journal ID (publisher-id): thno

Title: Theranostics

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1838-7640

Publication date Collection: 2017

Publication date (Electronic): 1 June 2017

Volume: 7

Issue: 8

Pages: 2186-2203

Affiliations

[1 ]College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea;

[2 ]Department of Dental Hygiene, Gwangyang Health Sciences University, Gwnagyang, Jeonnam 57764, Korea;

[3 ]Department of Molecular Biology, Dankook University, Yongin, Gyeonggi 16890, Korea;

[4 ]Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD 20850, USA;

[5 ]Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Korea.

Author notes

✉ Corresponding authors: Jin Tae Hong, PhD; Professor, College of Pharmacy & Medical Research Center, Chungbuk National University, 194-31 Osongsaengmyeong 1-ro, Osong-Biocampus Building Room 303, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk 28160, Korea, Telephone: 82-43-261-2813, FAX: 82-43-268-2732, E-mail: jinthong@ 123456chungbuk.ac.kr Professor, Do Young Yoon, Department of Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea, Telephone: 82-2-444-2188, FAX: 82-2-444-6176, E-mail: ydy4218@ 123456konkuk.ac.kr

*These authors contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: thnov07p2186

DOI: 10.7150/thno.18407

PMC ID: 5505053

PubMed ID: 28740544

SO-VID: 6c62cc70-adea-4901-94db-8b298b5474b6

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This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Interleukin-32α Inhibits Endothelial Inflammation, Vascular Smooth Muscle Cell Activation, and Atherosclerosis by Upregulating Timp3 and Reck through suppressing microRNA-205 Biogenesis

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Cancer Immunotherapy

Most cited references 50

The RNA-binding Protein KSRP Promotes the Biogenesis of a Subset of miRNAs

Endothelial cell functions.

Cytokines in atherosclerosis: Key players in all stages of disease and promising therapeutic targets

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