Table 3.

The roles of interleukins in atherosclerosis.

Interleukin	Summary of studies using mouse model systems	Ref.
IL-1α	BMT in the LDLR−/− model demonstrated that macrophage-derived IL-1α but not IL-1β drives atherosclerosis. BMT in the ApoE−/− model also demonstrated the importance of IL-1α. Fatty acid-induced uncoupling of mitochondrial respiration elicits inflammasome-independent IL-1α production that drives vascular inflammation in atherosclerosis. Active immunization targeting IL-1α decreases both the inflammatory reaction and plaque progression in the ApoE−/− model.	[82], [83], [84]
IL-1β	Deficiency or blocking of the cytokine in the ApoE−/− model decreases atherosclerosis and expression of several pro-inflammatory genes. Deficiency of IL-1 receptor-1 in the ApoE−/− model reduces atherosclerosis but was surprisingly associated with many unexpected features of plaque stability. BMT in this model showed that selective loss of IL-1 in the vessel wall reduces plaque burden.	[85], [86], [87], [88], [89], [90], [91]
IL-1RA	Overexpression in the LDLr−/− model reduces foam-cell lesion size by affecting plasma cholesterol levels. Overexpression in the ApoE−/− model attenuates fatty streak formation. The IL-1/IL-1RA ratio plays a crucial role in controlling vascular inflammation and atherosclerosis. Heterozygous deficiency in ApoE−/− mice enhances early atherosclerotic lesions with increased macrophage content and decreased level of SMCs. Deficiency in the C57BL/6J background promotes neointimal formation after wire injury.	[92], [93], [94], [95], [96], [97]
IL-2	Injection of the cytokine enhances atherosclerosis in the ApoE−/− model whereas injection of anti-IL-2 antibodies reduces this. Cytokine therapy with IL-2/anti-IL-2 monoclonal antibody in this model attenuates atherosclerosis by expanding Tregs and modulating immune-inflammatory components.	[98], [99]
IL-3	Transplantation of bone marrow from mice that are deficient in the common β subunit of the IL-3/GM-CSF receptor in the LDLr−/− model reduces stem cell expansion and monocytosis along with macrophage and collagen content.	[100]
IL-4	Early study showed that deficiency in the ApoE−/− model reduces atherosclerotic lesions. However, another in-depth study involving exogenous delivery and/or genetic deficiency in ApoE−/− or LDLr−/− models showed no involvement in atherosclerotic lesion formation irrespective of the mode of disease induction.	[101], [102]
IL-5	Transplantation of IL-15-deficient bone marrow in the LDLr−/− model reduces levels of IgM that recognizes epitopes in oxidized LDL and accelerates atherosclerosis.	[103]
IL-6	Injection of the cytokine in the ApoE−/− mice increases levels of pro-inflammatory cytokines and lesion size and use of IL-6 lentivirus demonstrated the ability to destabilize plaques. Inhibition of IL-6 trans-signaling using the inhibitor, soluble glycoprotein 130, reduces atherosclerosis by decreasing endothelial cell activation, infiltration of SMCs and recruitment of monocytes. However, deficiency of the cytokine in both ApoE−/− and LDLr−/− models enhanced atherosclerosis.	[104], [105], [106], [107], [108], [109]
IL-10	BMT in the LDLr−/− model showed deficiency of the cytokine accelerates atherosclerosis whereas its overexpression inhibits advanced lesions, decreases cholesterol and phospholipid oxidation products in the aorta along with monocytic activation and produces a shift to Th2 phenotype. Deficiency in the ApoE−/− model increases atherosclerosis associated with increased LDL levels, Th1 response, MMP and tissue factor activities, and markers of systemic coagulation and vascular thrombosis. Deficiency in the ApoE*3-Leiden mice leads to increased neointima surface following cuff-induced stenosis of the femoral artery. A marked inhibition of this along with reduction in plasma cholesterol levels and expression of several pro-inflammatory cytokines was produced by overexpression of IL-10. The cytokine also attenuates the response to wire carotid artery injury in wt mice. Gene therapy using IL-10 encoding viral vectors or plasmids in ApoE−/− or LDLr−/− models reduces atherosclerosis associated with decreased inflammation, oxidative stress, expression of pro-inflammatory markers and macrophage content of plaques.	[110], [111], [112], [113], [114], [115], [116], [117], [118]
IL-12	Blockade of function by vaccination in the LDLr−/− model reduces atherosclerosis with increased SMC and collagen content. Deficiency in the ApoE−/− model reduces lesion. Injection of the cytokine in the ApoE−/− model increases serum levels of anti-oxidized LDL antibodies and accelerates atherosclerosis.	[101], [119], [120]
IL-13	Administration of cytokine in LDLr−/− model promotes favorable plaque morphology by increasing lesional collagen content, decreasing VCAM-dependent monocyte recruitment and inducing M2 macrophage phenotype. Deficiency of the cytokine accelerates atherosclerosis.	[121]
IL-15	Neutralization of the cytokine in the LDLr−/− model using a DNA vaccination strategy reduces plaque size. Blockade of the cytokine increases intimal thickening following carotid artery injury in C57BL/6.	[122], [123]
IL-17	Studies on loss of SOCS3 expression in T-cells of LDLr−/− model demonstrated protective role of the cytokine in atherosclerosis. Transplantation of IL-17 receptor deficient bone marrow in the LDLr−/− model attenuates atherosclerosis whereas deficiency of the cytokine in the ApoE−/− model has no effect on plaque burden but attenuates vascular and systemic inflammation. In contrast, inhibition using neutralizing antibody in the ApoE−/− model prevents atherosclerotic lesion progression by reducing inflammatory burden and cellular infiltration, and improving lesion stability. Similarly, deficiency of the cytokine or its receptor in the ApoE−/− model reduces atherosclerosis and vascular inflammation whereas injection of IL-17 promotes the disease. IL-17 exacerbates ferric chloride-induced arterial thrombosis in rat carotid artery.	[124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134]
IL-18	Deficiency in the ApoE−/− model reduces atherosclerosis associated with decreased action of IFN-γ, more stable plaque phenotype and shift to Th2 immune response though a pro-atherogenic role was identified in one study. Administration potentiates atherosclerosis associated with elevated levels of IFN-γ and reduced plaque stability. Lack of endogenous IFN-γ ablated the effects of IL-18 on atherosclerosis. In vivo electrotransfer of an expression plasmid encoding IL-18 binding protein in the ApoE−/− model attenuates atherosclerosis.	[135], [136], [137], [138], [139], [140]
IL-19	Administration reduces atherosclerosis in the LDLr−/− model by promotiong Th2 polarization, decreasing leukocyte adhesion and suppressing pro-inflammatory gene expression. Also, reduces ligation-mediated neointimal hyperplasia by decreasing activation of SMCs.	[141], [142]
IL-20	Administration in the ApoE−/− model promotes atherosclerosis.	[143]
IL-25	Administration in the ApoE−/− model reduces atherosclerosis via modulation of innate immune responses.	[144]
IL-27	Deficiency of the cytokine or its receptor in the LDLr−/− model along with BMT and in vitro cell culture-based approaches showed that IL-27 inhibits atherosclerosis by attenuating macrophage activation, uptake of modified LDL and pro-inflammatory cytokine production. Transplantation of IL-27 receptor deficient bone marrow in the LDL−/− model increases atherosclerotic development by skewing immune responses towards Th17 cells.	[145], [146]
IL-33	Administration in the ApoE−/− model reduces atherosclerosis associated with decreased foam cell content and levels of IFN-γ, and increased levels of IL-4, -5 and -13. Cytokine produced a Th1 to Th2 shift and had higher levels of anti-OxLDL antibodies. Mice treated with a soluble decoy receptor that neutralizes IL-33 developed larger plaques. Action of IL-33 was mediated in a IL-5-dependent manner.	[147], [148]