Atherosclerotic lesions are characterized by the accumulation of oxidized LDL (OxLDL) and the infiltration of macrophages and T cells. Cytokine expression in the microenvironment of evolving lesions can profoundly contribute to plaque development. While the pro-atherogenic effect of T helper (Th) 1 cytokines, such as IFN-γ, is well established, the role of Th2 cytokines is less clear. Therefore, we characterized the role of the Th2 cytokine interleukin (IL)-13 in murine atherosclerosis. Here, we report that IL-13 administration favourably modulated the morphology of already established atherosclerotic lesions by increasing lesional collagen content and reducing vascular cell adhesion molecule-1 (VCAM-1)-dependent monocyte recruitment, resulting in decreased plaque macrophage content. This was accompanied by the induction of alternatively activated (M2) macrophages, which exhibited increased clearance of OxLDL compared to IFN-γ-activated (M1) macrophages in vitro. Importantly, deficiency of IL-13 results in accelerated atherosclerosis in LDLR−/− mice without affecting plasma cholesterol levels. Thus, IL-13 protects from atherosclerosis and promotes a favourable plaque morphology, in part through the induction of alternatively activated macrophages.

Heparin is an excellent inhibitor of P-and L-selectin binding to the carbohydrate determinant, sialyl Lewis x . As a consequence of its anti-selectin activity, heparin attenuates metastasis and inflammation. Here we show that fucosylated chondroitin sulfate (FucCS), a polysaccharide isolated from sea cucumber composed of a chondroitin sulfate backbone substituted at the 3-position of the ␤-D-glucuronic acid residues with 2,4-disulfated ␣-L-fucopyranosyl branches, is a potent inhibitor of P-and L-selectin binding to immobilized sialyl Lewis x and LS180 carcinoma cell attachment to immobilized P-and L-selectins. Inhibition occurs in a concentration-dependent manner. Furthermore, FucCS was 4 -8-fold more potent than heparin in the inhibition of the P-and L-selectin-sialyl Lewis The surface of carcinoma cells exhibits altered glycosylation patterns (1-5), often containing highly branched or sialylated oligosaccharides, especially fucosylated glycans such as sialylLewis X (Sia␣2-3Gal␤1-4(Fuc␣1-3)GlcNAc) and sialyl-Lewis a (Sia␣2-3Gal␤1-3(Fuc␣1-4)GlcNAc). The presence of these oligosaccharides in tumor cells directly correlates with a poor prognosis for cancer patients because of tumor progression and metastatic spread (1-5). The sLe X -oligosaccharides 4 from carcinoma cells act as ligands of the three members of the selectin family of cell adhesion molecules. E-, P-, and L-selectins are vascular receptors for certain normal glycoproteins that contain sialyl-Lewis x,a found on leukocytes and endothelium (6 -8). The selectins also participate in hematogenous metastasis by mediating the interactions of tumor cells with platelets and endothelium (1-3). Hematogenous metastasis occurs through a series of sequential events involving the intravasation of tumor cells into the bloodstream, evasion of innate immune surveillance, adhesion to vascular endothelium of distant organs with subsequent extravasation, and colonization of tissues. It has been proposed that these microemboli of tumor cells with platelets and leukocytes allow tumor cells to evade the immune defenses and eventually colonize distant organs, forming metastatic foci (9 -15). Several studies have shown that a few minutes after intravenous injection, tumor cells are detected in emboli inside pulmonary capillaries in association with platelets and fibrin.Studies from several groups have indicated that tumor metastasis in experimental animals is inhibited by heparin (16 -19). Some clinical studies have also shown a beneficial effect of heparin in some types of human cancer (20 -24). The antimetastatic effect of heparin does not reflect its anticoagulant activity (25, 26) but rather relates to the ability of heparin to inhibit the interaction of sialyl Lewis x,a -rich oligosaccharides on tumor cells with P-selectin on platelets (16,27). In the presence of heparin, tumor cells lose the protection conferred by platelets becoming susceptible to the potentially cytotoxic action of immune effector cells, which leads to the inhibition of metastasis. A single intravascul...

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