Several cytokines with relevance to CVD has been proven to be related to the pathogenesis of AT in SLE. In the following paragraphs we highlight some of the most likely significantly involved.
Plasmacytoid dendritic cells (pDC) activated by immune complexes containing nucleic acids secrete type I IFN (IFNα
) in SLE. Type I IFN causes differentiation of monocytes to myeloid-derived dendritic cell (mDC) and activation of autoreactive T and B cells. Patients with SLE have an increased expression of type I IFN-regulated genes because of a continuous production of IFNα
. Recent reports have demonstrated that elevated levels of type I IFNs (cytokines with potent antiproliferative and antiangiogenic effects, and associated with active SLE disease, and positivity for some autoantibodies) could lead to endothelial dysfunction through the promotion of a reduction in the number of endothelial progenitor cells (EPCs, responsible for the neovascularization in sites of endothelial injury), thus contributing to the increased CV risk observed in SLE [17
]. In that way, a recent study by Denny and coworkers [18
] showed that SLE patients displayed not only significant decreases in the number of circulating EPCs, but also significant impairments in the capacity of EPCs/CACs—circulating angiogenic cells to differentiate into mature ECs and synthesize adequate levels of proangiogenic molecules vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF). Moreover, that study showed that lupus EPCs/CACs had increased IFNα
expression. By contributing to endothelial disjunction/damage and inducing proinflammatory responses within the atherosclerotic plaque, IFNs could promote AT in patients with SLE.
The role of the type II interferon (IFNγ
)—whose expression is significantly increased in peripheral blood mononuclear cells (PBMCs) of SLE patients [19
]—in the progression of atherosclerosis has been well debated due to evidence conveying both pro- and antiatherogenic actions of the cytokine. Since IFNγ
, known to be a proinflammatory cytokine, can also display antiinflammatory properties [20
], it is likely that it acts in both ways in AT. These conflicting actions may well be gene-specific and it is known that approximately a quarter of all genes within the transcriptome of the macrophage, a key immune cell involved in AT, is sensitive to IFNγ
has been shown to influence many features of atherosclerosis such as foam cell formation, the adaptive Th1-specific immune response and plaque development [22
]. In the global context of AT, it is possible that its proatherogenic actions out-weight its antiatherogenic ones. Nevertheless, the precise role of this type of IFN in the development of AT in SLE patients remains to be analyzed.
IFNs are often profoundly dysregulated in SLE, and both IFNα
have been shown to induce B lymphocyte stimulator (BLyS) expression. BLyS (also known as the B cell-activating factor belonging to the TNF family, or BAFF [23
]) was identified as a novel TNF family ligand, and has proven to be a key factor in the selection and survival of B cells [23
]. The BLyS protein is expressed by a wide variety of cell types, including monocytes, activated neutrophils, T cells and DCs [27
]. Although standing levels of BLyS are constitutively generated, its expression and secretion can be potentiated by inflammatory cytokines, such as IL-2, TNFα
, and IFNγ
]. BLyS levels affect survival signals and selective apoptosis of autoantibody-producing B cells. High levels of BLyS may relax B cell selection and contribute to autoantibody production, exacerbating the SLE disease state. It has been hypothesised a potential cooperative action of BLyS and IFNs in the aetiology of SLE. Since BLyS is not known to have direct or immediate proinflammatory activities, changes in serum BLyS levels are unlikely to trigger acute inflammatory reactions and disease manifestations. However, it is possible than an increase in disease activity may lag behind increases in circulating BLyS levels due to indirect or “delayed” effects of BLyS in the systemic immune-inflammatory reactions of SLE. Nevertheless, the possible association between the overexpression of BLyS and the development and/or progression or AT or CVD in SLE patients remains elusive.
is both a proinflammatory and an immunoregulatory cytokine. TNFα
has differential effects on monocytes, on B cells, on T cells, and on dendritic cells, as well as on the process of programmed cell death. TNFα
is a growth factor for B lymphocytes, and B lymphocytes are able to produce significant amounts of TNFα
in an autocrine loop [32
may also exert a significant influence on B cells by its capacity to induce IL-6 [33
]. Moreover, TNFα
stimulation leads to increased production of IFNγ
, a cytokine with a clear-cut pathological role in SLE, as previously described [34
also constitutes an activating cytokine and a maturation factor of dendritic cells, which are essential in immune regulation and have also been implicated in autoimmunity in general, and in SLE in particular [35
]. In addition, the elevated circulating levels of TNFα
found in SLE patients have been found to be associated with high triglyceride and low HDL levels [36
]. Moreover, in a recent study by Rho and coworkers [37
] it was established a significant association between TNFα
expression levels and the severity of coronary calcium scores in SLE patients. Yet, that data should be further confirmed in a new cohort of patients, as a previous study by Roman et al. [38
] found no association among TNFα
, IL6, or CD40L and the presence of carotid plaque in SLE.
Nevertheless, because of its wide involvement in the activity of monocytes, dendritic cells, and lymphocytes as well as in the expression of other inflammatory cytokines involved in AT development, TNFα may be considered a major factor in SLE-related CVD, acting both by contributing to hypertriglyceridaemia and by promoting atherosclerosis-related inflammation.
Interleukin-6 (IL-6) is a pleiotropic cytokine with a wide range of biological activities that plays an important role in immune regulation and inflammation. Furthermore an association between IL-6 and lupus was demonstrated in murine models of SLE and blocking IL-6 improved lupus in all models tested [39
]. IL-6 is one of the most important B cell stimulating factors that induces the differentiation of T cells into effectors cells. Immunoglobulin and antiDNA antibody production in vitro by B cells from lupus patients has been demonstrated to be promoted by IL-6 and inhibited by antibodies against IL-6 or the IL-6 receptor. IL-6 is involved in the recruitment of inflammatory cells and lipid homeostasis and is associated with increased cardiovascular mortality and prognosis in the general population. Moreover, IL-6 drives c-reactive protein (CRP) production, which itself plays multiple roles, influencing key promoters of AT; moreover, it appears as an independent predictor of coronary events [40
]. However, the role of IL-6 in the pathogenesis of SLE-related AT is also controversial. Some authors found elevated IL-6 levels only in cases with increased CRP, concluding that it is part of the acute phase response [41
]. Others defend the idea that the relationship between IL-6 concentrations and the burden of AT in SLE patients represents more than an epiphenomenon, and that measurement of IL-6 provides supplementary information in this cohort of SLE patients [42
IL-17 is a pro-inflammatory cytokine which participates in the defence against certain pathogens, primarily extra-cellular bacteria and fungi [43
]. IL-17 is produced by several cell subsets including CD4+ T cells, CD8+ T cells, NK cells and neutrophils [43
]. In addition to its proinflammatory capacity, IL-17 exerts its effects through the recruitment of monocytes and neutrophils by increasing the local production of chemokines (IL-8, monocyte chemoattractant protein-1, growth-related oncogene protein-alpha) [44
], the facilitation of T cell infiltration and activation by stimulating the expression of intercellular adhesion molecule-1 [49
] as well as the amplification of the immune response by inducing the production of IL-6, prostaglandin E2, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor [50
]. Additionally, IL-17 synergizes with other cytokines, in particular with IL-1β
, and IFNγ
]. Th17 cells have been implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis [56
] and multiple sclerosis [57
], and recent evidence suggested that IL-17-mediated inflammation might play a role in the pathogenesis of SLE. Also abnormally high levels of IL-17 and IL-23 have been reported in human SLE sera [58
], and more recently it has been provided evidence that IL-17 production by T cells is increased in SLE patients [59
]. That study further described that double negative (C4-CD8-) T cells, which are expanded in the peripheral blood of patients with SLE [60
], represent major producers of IL-17, and that they undergo a vigorous proliferative response following stimulation.
A very recent study [61
] has demonstrated a concomitant presence of IL-17 and IFNγ
in patients and clinical specimens of coronary atherosclerosis, the presence of IL-17/IFNγ
dual-producing T cells within coronary plaques, and a synergistic effect of IL-17 and IFNγ
on elicitation of proinflammatory cytokine and chemokine production by cultured human VSMC. Thus an association of this cytokine with human coronary AT has been already established. However, its role in SLE-related AT remains to be evaluated.
Macrophage migration inhibitory factor (MIF) has emerged as a potential link between SLE and atherosclerosis development [10
]. Increased serum levels of MIF have been detected in SLE patients compared with healthy control individual. MIF is a pleiotropic cytokine with roles in several inflammatory diseases. MIF induces the pro-inflammatory mediators TNFα
, IL-1, IL-6 and MMPs. It can activate T cells, promote angiogenesis and induce proliferation of cells, while inhibiting p53 expression and apoptosis of the same cells [62
]. MIF can be induced by oxLDL, which is an initiating factor in atherogenesis, and so expression of MIF early on may enhance pro-inflammatory responses and lesion progression [63
The interaction between CD40 and CD40L is also an integral part of the inflammatory pathway in the vascular system. CD40 ligation on cells of the vascular wall promotes mononuclear cells recruitment and contributes to thrombosis in the setting of atherosclerosis [64
]. The co-stimulatory molecule CD40 ligand (CD40L, also called sCD154) is a member of the TNF family and participates in B cell differentiation and proliferation [65
] as well as in antibody isotype switching [66
]. The binding of CD40L to its receptor, CD40, is thought to also be involved in atherogenesis and atherosclerotic plaque rupture [67
]. Some reports indicated elevated serum concentrations of CD40L in patients with SLE compared to matched control subjects [70
]. CD40L has been found to be over expressed in T cells of patients with SLE [72
], and elevated concentrations of CD40 and CD40L have been found in atherosclerotic plaques in SLE patients [67
An important outcome derived from the studies reported on this area is that only for a few cytokines there is sufficient consistent data allowing classifying them as typically proatherogenic (IL6, IL17,IFNγ, TNFα, BAFF, MIF, etc) or antiatherogenic (IL-10), and that some cytokines (IFNγ, TNFα, IL4, IL-6) can exert pro- or antiatherogenic effects depending on the disease status. This knowledge can be used for improved early detection, prevention and treatment of atherosclerosis in SLE.