Table 1.

Effects of pro-inflammatory cytokines on cardiac fibroblasts.

Cytokine/Species	Effect	Mechanism	Ref.
IL-6/rat cardiac fibroblasts	IL-6 enhances collagen synthesis and myofibroblast formation.	IL-6 binds to gp130, leading to the phosphorylation of Janus kinase, activating cellular events.	[86]
IL-6/mouse cardiac fibroblasts	IL-6 promotes myofibroblast differentiation and the release of proinflammatory cytokines in culture. In vivo, treatment with an anti-IL-6 blocking antibody reduced myofibroblast infiltration in the infarct (and also attenuated neutrophil infiltration) but also increased the size of the infarct.	IL-6-induced phosphorylation of STAT3 upregulates the expression of hyaluronan synthesis that supports a myofibroblast phenotype in cultured fibroblasts.	[87]
IL-6/mouse cardiac fibroblasts	IL-6 promotes fibroblast activation and collagen synthesis.	In a co-culture model, macrophages stimulate cardiac fibroblasts to produce IL-6, which promotes TGF-β production and the downstream activation of Smad3 in fibroblasts.	[80]
IL-6/neonatal rat ventricular fibroblasts	IL-6 stimulates fibroblast proliferation and myofibroblast differentiation under hypoxia. Inhibition of IL-6 signaling with an IL-6 receptor inhibitor attenuates hypoxia-induced fibroblast proliferation and differentiation and collagen I expression.	In cultured fibroblasts exposed to hypoxia, the effects of IL-6 are attributed to the activation of TGFβ1, MMP2, and MMP9.	[88]
IL-6/human cardiac fibroblasts	IL-6 in endothelial cell-derived conditioned media increases collagen type I and fibronectin gene expression in cardiac fibroblasts. The addition of soluble gp130 to endothelial cell-derived conditioned media prevents IL-6-dependent collagen type I and fibronectin gene expression.	IL-6 in conditioned media from endothelial cells binds to soluble IL-6R to induce trans-IL-6 signaling in cardiac fibroblasts.	[89]
IL-6/rat cardiac fibroblasts	In contrast to the promigratory effects of IL-1β and TNF-α, IL-6 has no effect on fibroblast migration.	IL-6 does not stimulate the activation of mitogen-activated protein kinases that are involved in the regulation of cell migration.	[40]
IL-6/adult mouse ventricular fibroblasts.	IL-6 increases fibroblast adhesion and proliferation.	Cardiomyocyte-derived IL-6 acts in a paracrine manner to promote fibroblast proliferation in a cardiomyocyte/fibroblast co-culture model.	[90]
IL-6/neonatal mouse cardiac fibroblasts	IL-6 loss decreases fibroblast-myocyte adhesion in vitro and markedly upregulates fibroblast proliferation.	In a fibroblast/cardiomyocyte coculture system, IL-6/soluble IL-6R trans-signaling activates STAT3 in fibroblasts to modulate fibroblast proliferation and adhesion to cardiomyocytes.	[91]
IL1-β/mouse cardiac fibroblasts	IL1-β: (a) attenuates TGF-β-induced α-SMA expression and incorporation into stress fibers, (b) abrogates fibroblast-mediated collagen pad contraction and expression of periostin, and (c) promotes a matrix-degrading phenotype via stimulating MMP3 and MMP8 expression.	IL1-β acts via IL-1R1 to upregulate BAMBI, which acts to negatively regulate TGFβ signaling. IL1-β also downregulates endoglin signaling receptors.	[35]
IL1-β/adult rat cardiac fibroblasts	IL1-β augments the expression and activity of MMP-2, 3, and 9, alongside an increase in TIMP-1 expression, and enhances fibroblast migration.	IL1-β activates p38, ERK, and JNK MAP kinase pathways to stimulate MMP expression and migration.	[92]
IL-1β/neonatal and adult rat cardiac fibroblasts	IL1-β selectively downregulates the expression and synthesis of fibrillar collagens. Increases total MMP activity, with an increase in the expression of MMP-2, 9, and 13.	No mechanism is studied.	[93]
IL-1β/mouse cardiac fibroblasts	IL-1β stimulates proinflammatory gene expression. It promotes ECM remodeling.	IL-1β acts via IL-R1 to promote ECM remodeling via enhancing the fibroblast expression of MMPs (MMP-3, 8, and 9) and downregulating the expression of TIMP-2 and TIMP-4.	[94]
IL-1β/neonatal rat cardiac fibroblasts	IL-1β induces AT1 receptor upregulation in fibroblasts, contributing to ECM remodeling.	IL-1β acts via an NFκB-dependent mechanism to upregulate AT1R expression.	[95]
IL-1α/mouse neonatal ventricular fibroblasts	IL-1R antagonism and the administration of an anti-IL-1α blocking antibody show that the conditioned medium of necrotic cardiomyocytes activates proinflammatory signaling in fibroblasts through IL-1α.	IL-1α acts via an MyD88-dependent and NLRP3-independent pathway to promote pro-inflammatory gene expression in cardiac fibroblasts.	[43]
IL-1α/human cardiac fibroblasts	IL-1α markedly increases the expression of MMP-1, 3, 9, and 10, with a minimal effect on the mRNA expression of structural ECM proteins, and reduces the expression of ADAMTS1.	IL-1α acts via distinct P38 MAPK subtypes α/β/γ/δ to regulate the expression of MMPs and metalloproteinases in fibroblasts.	[96]
IL-1α/human cardiac fibroblasts	IL-1α stimulates proinflammatory gene expression in fibroblasts via upregulation of IL-1β, TNF-α, and IL-6.	ERK, JNK, and p38 MAPKs, along with nuclear factor (NF)-kB signaling, distinctly regulates IL1-β, TNF-α, and IL-6 expression.	[39]
IL-1α/human cardiac fibroblasts	Cardiac fibroblasts express neutrophil-binding adhesion molecules and neutrophil chemoattractants in response to IL-1α, promoting neutrophil recruitment into the infarcted myocardium.	IL-1α acts via a p38- and NF-κB-dependent mechanism to promote the expression of ICAM-1, E-selectin, and CXC chemokines in fibroblasts.	[97]
IL-1α/human cardiac fibroblasts	IL-1α has opposing effects on the expression of connective tissue growth factor (CTGF) and tenascin-C (TNC) expression.	Stimulates NFκB, PI3K/AKT, and p38 MAPK pathways to upregulate the expression of TNC while downregulating CTGF expression.	[83]
TNF-α/neonatal and adult rat cardiac fibroblasts	TNF-α promotes matrix degradation via mediating a decrease in collagen synthesis with an increase in MMP-2, MMP-9, and MMP-13. It has no effect on cell proliferation and total protein synthesis.	No mechanism studied.	[93]
TNF-α/neonatal rat cardiac fibroblasts	TNF-α increases AT1 receptor density in cardiac fibroblasts.	TNF-α acts via NFκB to increase AT1 receptor expression.	[95]
TNF-α/primary human fibroblasts from patient biopsies with dilated cardiomyopathy	(a) TNF-α increases cytokine expression at the transcriptome level; however, this increase was not reflected in the cytokine secretome. (b) TNF-α treatment has no effect on collagen/MMP/TIMP gene expression.	TNF-α effects are mediated via the transcriptional activation of NFκB.	[98]
TNF-α/rat cardiac fibroblasts	TNF-α stimulates a concentration-dependent increase in fibroblast migration.	TNF-α-dependent migration is regulated by the activation of MAPKs–ERK1/2, JNK, and p38.	[40]
TNF-α/human cardiac fibroblasts	TNF-α promotes fibroblast MMP-9 expression that is abrogated following treatment with an anti-TNF-α blocking antibody.	TNF-α acts via NFκB to promote the expression of MMP-9.	[99]
TNF-α/human cardiac fibroblasts	TNF-α promotes the proliferation of cardiac fibroblasts.	TNF-α-dependent activation of ERK1/2 and NFκB drives fibroblast cell proliferation.	[100]