A pro-fibrotic role for interleukin-4 in cardiac pressure overload

Kanellakis, Peter; Ditiatkovski, Michael; Kostolias, Gina; Bobik, Alexander

doi:10.1093/cvr/cvs142

Cited by 76 publications

(56 citation statements)

References 42 publications

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“…This finding is in line with a previous study showing that systemic administration of an anti-IL-4 neutralizing antibody did not affect the increased blood pressure in C57BL/6 mice with aortic coarctation. 13 Vascular endothelial cells express IL-4Rα and respond to IL-4. 14 In the lungs, IL-4 activates pulmonary endothelial cells and induces endothelin-1 production, resulting in the development of pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…13 This study established a causal relationship between IL-4 and cardiac fibrosis in hypertension. However, it remains unknown whether (1) chronically elevated IL-4, as seen in primary hypertension 5 and aging, 4 is sufficient to initiate fibrotic response, leading to cardiac fibrosis and dysfunction and (2) stress challenges, such as Ang II–induced hypertension, exacerbate IL-4–induced fibrotic cardiomyopathy, leading to heart failure.…”

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confidence: 87%

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Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction

et al. 2015

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Elevated interleukin-4 (IL-4) levels are associated with cardiac fibrosis in hypertension and heart failure in both patients and experimental animals. We hypothesized that chronically elevated IL-4 induces cardiac fibrosis, resulting in a predisposition of the heart to angiotensin II–induced damage. Wild-type Balb/c (WT, high circulating IL-4) and IL-4–deficient Balb/c mice (IL-4−/−) were used. WT mice exhibited cardiac fibrosis (evidenced by an increase in expression of procollagen genes/interstitial collagen fraction), enlarged left ventricle chamber, and declined cardiac function associated with a greater number of mast cells and macrophages in the heart compared with IL-4−/−. In contrast, IL-4−/− mice had normal cardiac architecture/function while showing a 57.9% reduction in heart interstitial collagen compared with WT, despite elevated proinflammatory cytokines in heart tissue. In response to angiotensin II administration, IL-4−/− had reduced interstitial myocardial fibrosis and were protected from developing dilated cardiomyopathy, which was seen in WT mice. This was associated with increased macrophage infiltration into the hearts of WT mice, despite a similar degree of hypertension and increased cardiac transforming growth factor-β1 in both groups. In vitro data demonstrated that IL-4 upregulates procollagen genes and stimulates collagen production in mouse cardiac fibroblasts. This process is mediated by signal transducer and activator of transcription 6 signaling pathway via IL-4 receptor alpha. This study not only establishes a causal relationship between IL-4 and cardiac fibrosis/dysfunction, but also reveals a critical role for IL-4 in angiotensin II–induced cardiac damage. IL-4 could serve as an additional target for the treatment of cardiac fibrosis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 87%

Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction

et al. 2015

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“…Activated mast cells release a wide variety of granule-stored bioactive mediators, cytokines and growth factors which have been demonstrated to stimulate cardiac fibroblast proliferation and collagen synthesis [86]. Mast cell granules contain large amounts of TNF-α [87], TGF-β, IL-4 [88], PDGFs and FGFs; however, these fibrogenic mediators are also synthesized by many other cell types involved in cardiac fibrosis, including macrophages and lymphocytes. Thus, their contribution to the cardiac fibrotic response remains unknown.…”

Section: The Cellular Effectors Of Cardiac Fibrosismentioning

confidence: 99%

The pathogenesis of cardiac fibrosis

Kong

Christia

Frangogiannis

2013

Cell. Mol. Life Sci.

1,296

1,147

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Cardiac fibrosis is characterized by net accumulation of extracellular matrix proteins in the cardiac interstitium and contributes to both systolic and diastolic dysfunction in many cardiac pathophysiologic conditions. This review manuscript discusses the cellular effectors and molecular pathways implicated in the pathogenesis of cardiac fibrosis. Although activated myofibroblasts are the main effector cells in the fibrotic heart, monocytes/macrophages, lymphocytes, mast cells, vascular cells and cardiomyocytes may also contribute to the fibrotic response by secreting key fibrogenic mediators. Inflammatory cytokines and chemokines, reactive oxygen species, mast cell-derived proteases, endothelin-1, the renin/angiotensin/aldosterone system, matricellular proteins and growth factors (such as TGF-β and PDGF) are some of the best-studied mediators implicated in cardiac fibrosis. Both experimental and clinical evidence suggests that cardiac fibrotic alterations may be reversible. Understanding the mechanisms responsible for initiation, progression and resolution of cardiac fibrosis is crucial to design anti-fibrotic treatment strategies for patients with heart disease.

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“…Inhibition of IL-4 with neutralizing antibodies attenuated cardiac fibrosis and hypertrophy during pressure overload, suggesting that IL-4 is pro-fibrotic and may exacerbate the hypertrophic response. 72 The effect of blocking IL-4 signaling in macrophages, and its response in hypertrophic remodeling is unknown. The important effectors of this response are unclear since multiple cell types respond to IL-4, and further analysis using conditional targeting strategies will be necessary to understand how IL-4 signaling regulates specific cell types.…”

Section: Regulation Of Hypertrophic Remodeling By Macrophage and Myelmentioning

confidence: 99%