Cytokines and atherosclerosis: a comprehensive review of studies in mice

Abstract

In the past few years, inflammation has emerged as a major driving force of atherosclerotic lesion development. It is now well-established that from early lesion to vulnerable plaque formation, numerous cellular and molecular inflammatory components participate in the disease process. The most prominent cells that invade in evolving lesions are monocyte-derived macrophages and T-lymphocytes. Both cell types produce a wide array of soluble inflammatory mediators (cytokines, chemokines) which are critically important in the initiation and perpetuation of the disease. This review summarizes the currently available information from mouse studies on the contribution of a specified group of cytokines expressed in atherosclerotic lesions, viz. interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IL-20) and macrophage-associated cytokines [tumour necrosis factor-alpha (TNF-alpha); macrophage migration inhibitory factor (MIF); interferon-gamma (IFN-gamma); colony stimulating factors G-CSF,-M-CSF,-GM-CSF) to atherogenesis. Emphasis is put on the consistency of the effects of these cytokines, i.e. inasmuch an effect depends on the experimental approach applied (overexpression/deletion, strain, gender, dietary conditions, and disease stage). An important outcome of this survey is (i) that only for a few cytokines there is sufficient consistent data allowing classifying them as typically proatherogenic (IL-1, IL-12, IL-18, MIF, IFN-gamma, TNF-alpha, and M-CSF) or antiatherogenic (IL-10) and (ii) that some cytokines (IL-4, IL-6 and GM-CSF) can exert pro- or anti-atherogenic effects depending on the experimental conditions. This knowledge can be used for improved early detection, prevention and treatment of atherosclerosis.

Figure 1

Cytokines involved in atherogenesis and their cellular source and targets. (1) LDL particles penetrate the endothelial cell layer and are oxidized in the intima (oxLDL). Pro-inflammatory lipids are released from oxLDL and induce expression of cytokines in EC (e.g. IL-1, MIF, M-CSF, and GM-CSF) and SMCs (M-CSF). MIF and M-CSF can function as a chemotactic factor for monocytes and T-cells. GM-CSF is a major regulator of dendritic cell differentiation and involved in lesional dendritic cell accumulation. (3) TNF-α and MIF are involved in the autocrine activation of macrophages thereby amplifying inflammation. IL-12 and IL-18 formed by macrophages and IL-4 (e.g. from NKT) promote the differentiation of native T-cells into T_H1-cells and T_H2-cells, respectively. IL-12 and IL-18 are potent inducers of IFN-γ. (4) T_H1-cells can further activate macrophages (inflammatory cascade) whereas T_H2-cells produce anti-inflammatory mediators (e.g. IL-4, IL-10, and IL-13) with opposite effect on macrophages, T-cells and EC. IL-4 (T_H2-associated) impair the development of T_H1-cells from pre-T_H-cells (not shown). Vice versa, IFN-γ inhibits T_H2-cell development. Also, T_H2-derived IL-4 and IL-13 are potent stimulators of antibody production (on B-cells, not shown), IL-5 is involved in B-cell differentiation and eosinophilic inflammation. (5) Macrophages are further stimulated by T-cell derived IFN-γ as well as IL-1 and TNF-α (also from other sources) together resulting in an amplification of the inflammatory response. (6) SMCs are targets for many of the macrophage- and T-cell-derived cytokines and participate in this self-perpetuating inflammatory cycle by producing and secreting a range of pro-inflammatory factors among which are IL-1, TNF-α, and IFN-γ.

Figure 2

Categorization of cytokines into pro-atherogenic and anti-atherogenic cytokines based on their effects in mouse atherosclerosis models. (A) The balance between pro-inflammatory and anti-inflammatory cytokines is crucial for lesion development and imbalance is colloquially referred to exacerbate atherosclerotic disease. (B) Overview of the cytokines with consistent anti-atherogenic effects (green circle), pro-atherogenic effects (red circle), or variable, dual function (intersection).