Effects of interleukin-1 on cardiac fibroblast function: Relevance to post-myocardial infarction remodelling

Abstract

The cardiac fibroblast (CF) is a multifunctional and heterogeneous cell type that plays an essential role in regulating cardiac development, structure and function. Following myocardial infarction (MI), the myocardium undergoes complex structural remodelling in an attempt to repair the damaged tissue and overcome the loss of function induced by ischemia/reperfusion injury. Evidence is emerging that CF play critical roles in all stages of post-MI remodelling, including the initial inflammatory phase that is triggered in response to myocardial damage. CF are particularly responsive to the proinflammatory cytokine interleukin-1 (IL-1) whose levels are rapidly induced in the myocardium after MI. Studies from our laboratory in recent years have sought to evaluate the functional effects of IL-1 on human CF function and to determine the underlying molecular mechanisms. This review summarises these data and sets it in the context of post-MI cardiac remodelling, identifying the fibroblast as a potential therapeutic target for reducing adverse cardiac remodelling and its devastating consequences.3

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…Thus, CF may contribute to the inflammatory milieu that occurs in the myocardium early after MI [10,95]. In addition to this inflammatory response, we [7,88,93,94,[96][97][98] and others [61,99,100] have demonstrated that CF alter the balance of cardiac ECM turnover in favour of degradation in response to IL-1; for example by increasing secretion of MMPs, decreasing collagen synthesis and decreasing expression of profibrotic factors (e.g. connective tissue growth factor).…”

“…Thus, IL-1 is emerging as a potentially important therapeutic target for controlling both inflammatory and fibrotic responses after MI through effects on CF [88]. A similar role for IL-1 in atherosclerosis has also been proposed [101], making IL-1-selective inhibitory strategies an attractive proposition for treating a range of cardiovascular diseases.…”

“…We have previously demonstrated that human CF are very responsive to IL-1 [88], which is expressed by cardiomyocytes [89] and CF [90] and can act as a DAMP when released from damaged or dying cells [67,87]. In response to IL-1 stimulation, human CF secrete a host of proinflammatory cytokines (e.g.…”

“…IL-1 , IL-6, TNF-) and neutrophilattracting chemokines (e.g. CXCL-1, 2, 5 and 8), and express specific neutrophil-binding adhesion molecules including ICAM-1 and E-selectin [88,[90][91][92][93], as well as the matricellular protein TN-C [94]. Thus, CF may contribute to the inflammatory milieu that occurs in the myocardium early after MI [10,95].…”

Investigating inherent functional differences between human cardiac fibroblasts cultured from nondiabetic and Type 2 diabetic donors

“…IL-1 is a proinflammatory cytokine whose levels are increased in the heart early after myocardial infarction and can modulate many cellular functions of CF that are pertinent to cardiac remodelling [27]. Using real-time RT-PCR we assessed the influence of T2DM on mRNA expression of several pertinent genes at basal level and following treatment with IL-1.…”