Table 1.

The role and signaling pathway of crucial cytokines in atherosclerosis development.

Cytokine	Pro- or anti-atherogenic	Role in atherosclerosis development	Signaling pathway	Reference
IFN-γ	Pro-	Can induce the pro-inflammatory M1 phenotype in macrophages. It is able to increase foam cell formation by attenuating the expression of key genes implicated in macrophage cholesterol efflux and increase the expression of those involved in the uptake of cholesterol. Contributes to the continuously growing plaque size by inducing foam cell apoptosis which causes them to ‘spill’ their lipid content into the core of the plaque.	JAK-STAT	[7–14]
CCL2	Pro-	Also known as MCP-1. It is one of the major chemokines involved in monocyte recruitment during atherosclerosis development. Deficiency of CCL2 in atherosclerotic mouse models markedly attenuates disease development when CX3CL1 and CCL5 are also knocked out. Mouse models lacking CCL2 or its receptor develop smaller atherosclerotic plaques.	PKC/ERK1/2/NF-κB	[15,16]
IL-1β	Pro-	It is able to induce the pro-inflammatory M1 macrophage phenotype. oxLDL has been shown to stimulate IL-1β secretion in human macrophages. It is a major activator of the innate immune response. The expression of several pro-inflammatory genes can be induced by IL-1β. It also exerts an auto-inflammatory response by inducing its own expression.	NF-κB/JNK/p38 MAPK	[9–11,17–21]
TGF-β	Anti-	The anti-inflammatory M2 macrophage releases TGF-β. Its over expression in ApoE-/- mice results in smaller plaque, whereas the inverse occurs in ApoE-/- mice that are deficient for the TGF-β receptor.	SMAD-dependent or SMAD-independent	[9–11,22–24]
IL-33	Anti-	IL-33 is capable of attenuating foam cell formation by stimulating macrophage cholesterol efflux and attenuating cholesterol uptake. ApoE-/- mice injected with IL-33 have a reduced number of foam cells present in their atherosclerotic lesions. Neutralization of IL-33 increases atherosclerosis.	ST2/IL-1RAcP/MyD88 or ERK1/2 or p38 MAPK or NF-κB	[6,25–29]

ApoE, Apolipoprotein E; CCL, Chemokine (C-C motif) ligand; PKC, Protein kinase C; CX₃CL, Chemokine (C-X3-C motif) ligand; ERK, Extracellular signal-regulated kinase; IFN, Interferon; IL, Interleukin; IL-1RAcP, IL-1 receptor accessory protein; JAK, Janus kinase; JNK, c-JUN N-terminal kinases; MAPK, Mitogen activated protein kinases; MCP-1, Monocyte chemoattractant protein-1; MyD88, Myeloid differentiation primary response gene 88; NF-κB, Nuclear factor kappa-light-chain-enhancer of activated B cells; oxLDL, oxidized low density lipoprotein; STAT, Signal transducer and activator of transcription; TGF, Transforming growth factor.