High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation?
Introduction
In chronic inflammation, the production of cytokines by infiltrating and resident tissue cells escapes regulatory mechanisms, while leading to tissue destruction either directly or indirectly through the activation of immune and inflammatory cells, e.g. by inducing them to produce inflammatory cytokines and proteases that are implicated in tissue destruction. The activity of pro-inflammatory cytokines may be counterbalanced by: (a) cytokine inhibitors interfering with the binding of the cytokine to its specific receptor; and/or (b) inhibitory (anti-inflammatory) cytokines, which are biologically active by affecting the synthesis of pro-inflammatory cytokines and their inhibitors and/or the target cell activation [1]. It is generally claimed that an imbalance between cytokines and their respective inhibitors is characteristic of chronic inflammatory conditions. Cytokines are involved in the triggering of the immune response, induction of acute inflammatory events and transition to or persistence of chronic inflammation. There is now considerable evidence that cytokines such as TNF and IL-1 contribute to the pathogenesis of RA [2] and MS [3], although in the latter, TNF-α might also play a part in tissue repair. These cytokines are also involved in SLE [4], vasculitis [5] and atherosclerosis [6]. This implies that to safeguard healthy conditions the mechanisms triggering cytokine production need to be controlled.
Section snippets
Triggering of cytokine production in chronic inflammation
Inflammation is usually the consequence of tissue damage and its purpose is to direct plasma factors and immune cells to the lesion site to eradicate infection and to repair damaged tissue. In acute inflammation, the production of IL-1 and TNF-α at high levels is induced by endotoxins such as lipopolysaccharides (LPS). In chronic inflammation, infiltration of the target tissue by immune cells precedes tissue damage, i.e. the lesion occurs after infiltration by immune cells. Based on
Modulation of contact-mediated induction of cytokines in monocytes by stimulated T lymphocytes
Since the contact-mediated activation of monocyte-macrophages is a major pathway inducing cytokine production, the modulation of this mechanism, i.e. the blockade of IL-1 and TNF-α production at the level it is triggered, would be of therapeutic interest. We established that therapeutic agents used in RA and MS patients, i.e. leflunomide (LF) and IFN-β [13], [14], affect the contact-mediated activation of monocytes. Both LF and IFNβ inhibit the ability of stimulated T lymphocytes to trigger
Control of contact-mediated activation of monocytes
Recently we identified a novel mechanism of inhibition resulting from the hindrance of cellular contact between stimulated T cells and monocytes by high-density lipoprotein (HDL)-associated apolipoprotein A-I (apo A-I) [18]. The latter mechanism inhibits monocyte activation and thus both TNF-α and IL-1β production. This suggests that, in analogy with other homeostatic systems, natural inhibitors (at least apo A-I) interfere with the lymphocyte/monocyte interaction. The fact that this inhibitory
HDL and apo A-I in chronic inflammatory diseases
The inhibition of T cell-signaling of monocytes might be important in maintaining a low level of monocyte activation within the blood stream. Variations of apo A-I concentration were observed in several inflammatory diseases. In RA, the levels of circulating apo A-I and HDL-cholesterol in untreated patients are lower than in normal controls [20], [21], [22]. In contrast, apo A-I is enhanced in synovial fluid of RA patients [23], although its concentrations remained 10-fold lower in synovial
HDL: the missing link between infection and chronic inflammation?
In addition to its anti-inflammatory effect in contact-mediated activation of monocyte-macrophages, HDL are effective in inhibiting the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in TNF-α- or LPS-stimulated human vascular endothelial cells (HUVEC) [32]. In the latter system, HDL again display anti-inflammatory functions in both infectious and non-infectious conditions. Indeed, it is well known that HDLs exhibit anti-inflammatory
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