Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction

Abstract

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.

Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis

“…By examining differentially expressed signaling genes in the heat map (Fig. 3b, c), day 0 fibroblasts use Pik3r4 and Stat5 signaling, while MI day 1 fibroblasts use Tnfrsf9 (CD137) signaling to induce inflammation [20], MI day 3 fibroblasts use interleukin-4 receptor alpha ( Il4ra ) signaling to stimulate anti-inflammatory and pro-fibrotic wound healing [44], and MI day 7 fibroblasts use Pik3r3 signaling to mediate TGFβ1 effects [65] and Fgfr2 to regulate PI3K signaling [42].

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Differential Regulation of Cardiac Function and Intracardiac Cytokines by Rapamycin in Healthy and Diabetic Rats

“…Increased expression of IL-1 alpha and IL-1 beta is associated with poor prognosis for heart failure and suppression of IL-1 beta is reported to reduce leukocyte production and inflammation after acute myocardial infarction [25, 26]. IL-4 is implicated in cardiac fibrosis [27]. These interleukins were suppressed in the heart tissues of ZO-C compared to ZL-C (Figure 4).…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Although not well studied, the engagement of adaptive immunity by ANG II may also impact on cardiac hypertrophy and overall structural remodeling of the heart. For instance, the pathogenesis of ANG II-induced dilated cardiomyopathy was reported to depend on the T cell Th2 phenotype (816) and to involve the Th2 polarizing cytokine IL-4 (815). Others recently showed that B cells have a contributory role in an ANG II-induced model of heart failure (186).…”