Abstract
Cardiac fibroblasts (CFs) contribute to theinflammatory response to tissue damage, secreting both pro- and anti-inflammatory cytokines and chemokines. Interferon beta (IFN-β) induces the phosphorylation of signal transducer and activator of transcription (STAT) proteins through the activation of its own receptor, modulating the secretion of cytokines and chemokines which regulate inflammation. However, the role of IFN-β and STAT proteins in modulating the inflammatory response of CF remains unknown. CF were isolated from adult male rats and subsequently stimulated with IFN-β to evaluate the participation of STAT proteins in secreting chemokines, cytokines, cell adhesion proteins expression and in their capacity to recruit neutrophils. In addition, in CF in which the TRL4 receptor was pre-activated, the effect of INF-β on the aforementioned responses was also evaluated. Cardiac fibroblasts stimulation with IFN-β showed an increase in STAT1, STAT2, and STAT3 phosphorylation. IFN-β stimulation through STAT1 activation increased proinflammatory chemokines MCP-1 and IP-10 secretion, whereas IFN-β induced activation of STAT3 increased cytokine secretion of anti-inflammatory IL-10. Moreover, in TLR4-activated CF, IFN-β through STAT2 and/or STAT3, produced an anti-inflammatory effect, reducing pro-IL-1β, TNF-α, IL-6, MCP-1, and IP-10 secretion; and decreasing neutrophil recruitment by decreasing ICAM-1 and VCAM-1 expression. Altogether, our results indicate that IFN-β exerts both pro-inflammatory and anti-inflammatory effects in non-stimulated CF, through differential activation of STAT proteins. When CF were previously treated with an inflammatory agent such as TLR-4 activation, IFN-β effects were predominantly anti-inflammatory.
Highlights
The classical role of cardiac fibroblasts (CFs) is extracellular matrix (ECM) protein homeostasis
The primary antibodies for p-Stat1, p-Stat2, and p-Stat3 were purchased from Cell Signaling Technology (Boston, MA, United States)
To assess whether signal transducer and activator of transcription (STAT) phosphorylation was dependent on the activation of JAK/STAT signaling pathway by IFN-β through activation of IFN-β receptor (IFNAR), Cardiac fibroblasts (CFs) were pretreated with 100 or 500 nM of JAK inhibitor Ruxolitinib, which inhibited IFNβ-induced STAT1, STAT2, and STAT3 protein phosphorylation (Figures 1D–F)
Summary
The classical role of cardiac fibroblasts (CFs) is extracellular matrix (ECM) protein homeostasis. Inflammatory Role of IFN-β Cardiac Fibroblast necessary for repair, secreting pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), as well as pro-inflammatory chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin (Kukielka et al, 1995). CF secrete inhibitory mediators capable of suppressing pro-inflammatory signals, such as interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) (Dewald et al, 2005; Nahrendorf et al, 2007; Turner et al, 2009, 2010). Interferon beta (IFN-β) is a cytokine produced by innate immune cells, including macrophages and dendritic cells, as well as non-immune cells, such as fibroblasts and epithelial cells (Ivashkiv and Donlin, 2014). IFN-β elicits a wide range of effects, including anti-inflammatory and pro-inflammatory responses, and regulates the development and activation of virtually all innate and adaptive immune effector cells. The effects of IFN-β on non-immune cells such as CF remain unknown
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