p38 MAPK alpha mediates cytokine-induced IL-6 and MMP-3 expression in human cardiac fibroblasts

Sinfield, John K.; Das, Anupam; O’Regan, David; Ball, Stephen G.; Porter, Karen E.; Turner, Neil A.

doi:10.1016/j.bbrc.2012.11.071

Cited by 47 publications

(54 citation statements)

References 34 publications

(31 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The remodeling heart is characterized by increased levels of various proinflammatory cytokines, such as interleukin (IL)-1, IL-6 and tumor necrosis factor α (TNFα) (Nicoletti and Michel, 1999;Porter and Turner, 2009;Souders et al, 2009). CF actively contribute to this inflammatory milieu by secreting various cytokines and chemokines, which attract and activate immune cells (Sinfield et al, 2013;Turner et al, 2011;Turner et al, 2009;Turner et al, 2010). On the other hand, elevated levels of anti-inflammatory factors such as transforming growth factor β1 (TGFβ1), derived from both infiltrating immune cells and myocardial cells, reduce inflammation and lead to differentiation of CF to myofibroblasts (CMF) (Leask, 2010;Lijnen et al, 2000;van den Borne et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, IL-1α induced metalloproteinases MMP1, MMP3, MMP9 and MMP10 (Sinfield et al, 2013;Turner et al, 2010); indicating that increased levels of this cytokine have important consequences for ECM degradation. Increased MMP expression and activity was also observed in rat CF stimulated by IL-1β (Brown et al, 2007) or TNFα (Siwik et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

et al. 2013

Self Cite

View full text Add to dashboard Cite

A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractDuring cardiac remodeling, cardiac fibroblasts (CF) are influenced by increased levels of interleukin-1α (IL-1α) and transforming growth factor-β1 (TGFβ1). The present study investigated the interaction between these two important cytokines on function of human CF and their differentiation to myofibroblasts (CMF). CF were isolated from human atrial appendage and exposed to IL-1α and/or TGFβ1 (both 0.1 ng/ml). mRNA expression levels of selected genes were determined after 6-24 h by real-time RT-PCR, while protein levels were analyzed at 24-48 h by ELISA or Western blot.Activation of canonical signaling pathways (NFB, Smad3, p38 MAPK) was determined by Western blotting. Differentiation to CMF was examined by collagen gel contraction assays. Exposure of CF to IL-1α alone enhanced levels of IL-6, IL-8, matrix metalloproteinase-3 (MMP3) and collagen III (COL3A1), but reduced the CMF markers α-smooth muscle actin (αSMA) and connective tissue growth factor (CTGF/CCN2). By contrast, TGFβ1 alone had minor effects on IL-6, IL-8 and MMP3levels, but significantly increased levels of the CMF markers αSMA, CTGF, COL1A1 and COL3A1.Co-stimulation with both IL-1α and TGFβ1 increased MMP3 expression synergistically. Furthermore, while TGFβ1 had no effect on IL-1α-induced IL-6 or IL-8 levels, co-stimulation inhibited the TGFβ1-induced increase in αSMA and blocked the gel contraction caused by TGFβ1. Combining IL-1α and TGFβ1 had no apparent effect on their canonical signaling pathways. In conclusion, IL-1α and TGFβ1 act synergistically to stimulate MMP3 expression in CF. Moreover, IL-1α has a dominant inhibitory effect on the phenotypic switch of CF to CMF induced by TGFβ1.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Interleukin-1mentioning

confidence: 78%

“…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].…”

Section: Interleukin-1mentioning

confidence: 99%

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

Turner

2016

Journal of Molecular and Cellular Cardiology

Self Cite

168

124

View full text Add to dashboard Cite

Cardiac fibroblasts (CF) are well-established as key regulators of extracellular matrix (ECM) turnover in the context of myocardial remodelling and fibrosis. Recently, this cell type has also been shown to act as a sensor of myocardial damage by detecting and responding to damage-associated molecular patterns (DAMPs) upregulated with cardiac injury. CF express a range of innate immunity pattern recognition receptors (TLRs, NLRs, IL-1R1, RAGE) that are stimulated by a host of different DAMPs that are evident in the injured or remodelling myocardium. These include intracellular molecules released by necrotic cells (heat shock proteins, high mobility group box 1 protein, S100 proteins), proinflammatory cytokines (interleukin-1), specific ECM molecules up-regulated in response to tissue injury (fibronectin-EDA, tenascin-C) or molecules modified by a pathological environment (advanced glycation end product-modified proteins observed with diabetes). DAMP receptor activation on fibroblasts is coupled to altered cellular function including changes in proliferation, migration, myofibroblast transdifferentiation, ECM turnover and production of fibrotic and inflammatory paracrine factors, which directly impact on the heart's ability to respond to injury. This review gives an overview of the important role played by CF in responding to myocardial DAMPs and how the DAMP/CF axis could be exploited experimentally and therapeutically.3

show abstract

“…We therefore investigated the role of individual p38 MAPK subtypes in mediating IL-1-induced IL-6 and MMP-3 gene expression in human CF (Sinfield et al, 2013). Quantitative RT-PCR and Western blotting of cells from multiple patients revealed a consistent pattern of p38 subtype 17 expression in human CF, with p38- being most abundant, followed by p38- and p38-, and little or no expression of p38-β (Sinfield et al, 2013). This pattern of subtype expression is similar to that of whole heart tissue from adult humans (Lemke et al, 2001).…”

Section: Il-1 Signalling In Cfmentioning

confidence: 99%

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

Turner

2014

Vascular Pharmacology

Self Cite

View full text Add to dashboard Cite

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

show abstract

p38 MAPK alpha mediates cytokine-induced IL-6 and MMP-3 expression in human cardiac fibroblasts

Cited by 47 publications

References 34 publications

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

Combined effects of interleukin-1α and transforming growth factor-β1 on modulation of human cardiac fibroblast function

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

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

Contact Info

Product

Resources

About