Interleukin-33 Induces Expression of Adhesion Molecules and ...

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mast cells, eosinophils and basophils, as well as release of different cytokines from these cells, and is a chemoattractant for Th2 cells in vitro. 19–22,49 Furthermore, it was shown recently that IL-33 upregulated cell surface expression of the adhesion molecule ICAM-1 on eosinophils, but it suppressed that of ICAM-3 and L-selectin. 47 In an in vivo experimental sepsis model, IL-33 treatment increased neutrophil influx into the peritoneal cavity and induced more efficient bacterial clearance, which was associated with reduced mortality. 50 In a murine model of collageninduced arthritis, IL-33 treatment markedly exacerbated mononuclear and polymorphonuclear cell infiltration into the joint which was associated with disease progression. 51 Taken together, IL-33 appears to be an important immune regulator that plays a role in inflammation, especially in the rapid recruitment of certain effector cells into sites of ongoing inflammation. Compared to these effects of IL-33 on the immune system, data on its contribution to cardiovascular pathophysiology is scarce. In human endothelial cells, IL-33 induced inflammatory activation as evidenced by increased vascular permeability, increased production of inflammatory cytokines, and the stimulation of angiogenesis. 27,31 A possible role for IL-33 in the development and progression of atherosclerosis is suggested but not well characterized yet. IL-33 was shown to be expressed in cells that are known to be present in atherosclerotic lesions and to activate such cells. 2,3 For example, IL-33 was found in coronary artery endothelium, 29 and was shown to induce the production of proinflammatory cytokines from human mast cells and T-cells and to enhance lipopolysaccharide (LPS)-induced TNF-�, IL-6, and IL-1� production from macrophages. 24,52,53 It should be noted that recently generated IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. 54 Furthermore, IL-33 mRNA expression was found in human endothelial cells, coronary artery smooth muscle cells, and peripheral blood monocytes and leukocytes. 13,28,29,55 In contrast to our data presented here, which suggest a detrimental contribution of IL-33 to the early development of atherosclerosis, in ApoE �/� mice fed on a high-fat diet treatment with IL-33 had reduced atherosclerotic lesions in the thoracic aorta via increased IL-5 and oxidized low density lipoprotein auto-antibody production as well as by decreased macrophage foam cell formation. 28,30 It should be noted, however, that in these latter studies, which showed antiatherosclerotic effects of long-term administration (6 weeks) of IL-33, 1 �g/injection of the cytokine was administered into ApoE �/� mice that already had developed atherosclerosis. 28,30 IL-33 administration increased Th2 cytokines, IL-4, IL-5, and IL-13, and reduced the Th1 cytokine IFN-� by lymph node cells in vitro and in serum ex vivo. 28 The level of the Th17 cytokine IL-17 was not different in lymph node cells between IL-33- and PBS-treated animals, and IL-17 and IL-10 serum levels were not detectable. Local cytokine expression in the vasculature ex vivo was not investigated in this study. There is strong evidence supporting a proatherogenic role of Th1 cells, whereas a possible contribution of the Th2 Demyanets et al IL-33 Induces Adhesion Molecules in Endothelial Cells 2087 subset in atherosclerotic lesion formation is controversially discussed. 45,56 The role of the Th2 pathway in the development of atherosclerosis seems to be depending on the stage and site of the lesion, and on the experimental model. 57 Both anti- and proatherogenic effects of IL-4, another prototypical Th2 cytokine, and IL-17, a cytokine produced by Th17 cells, were shown in different studies using different experimental approaches. 57 It should be noted that Th2 cell induction is promoted in severe hyperlipidemia, 58 and under these conditions Th2 cytokines could be a target for IL-33 as shown in this experimental mouse model of atherosclerosis. 28,30 These contradictory findings could be also explained on the basis of different roles for IL-33 and ST2 in distinct ST2-expressing cells. In support of that concept, IL-33 is able to enhance the production of the Th1 cytokine IFN-� by natural killer cells and invariant cells, 22,59 which are found in atherosclerotic lesions and are thought to be involved in the pathogenesis of atherosclerosis. 60 It is of interest that in our study recombinant human IL-33 at 100 ng/mL did not affect the production of the Th2 cytokines IL-4 and IL-5 and the T regulatory cytokine IL-10 in human coronary artery endothelial cells. Upregulation of adhesion molecules and chemokines in endothelial cells as shown here by us is, besides an impaired vasomotor function, a key event in endothelial dysfunction that is considered to be an early hallmark in the pathogenesis of atherosclerosis. 2,3 It should also be emphasized that in one of the articles mentioned above IL-33 injection into the mice enhanced their IL-6 serum levels. 28 IL-6 has been shown to contribute to development of atherosclerotic lesions, and its serum levels correlate with poor prognosis in humans with cardiovascular disease and are an independent predictor of sudden death in asymptomatic men. 61–63 Furthermore, it should be noted that IL-33 was shown to be associated with other human inflammatory pathologies such as rheumatoid arthritis, systemic sclerosis, inflammatory bowel disease, chronic pancreatitis, asthma, psoriasis, and anaphylactic shock. 23,24 However, the mechanisms of the deleterious effects of IL-33 in these disorders are not completely understood yet. In conclusion, we provide evidence for the first time that the latest member of the IL-1 cytokine family, the “alarmin” IL-33, 14,16 is present in human atherosclerotic lesion and stimulates the expression of the adhesion molecules ICAM-1, VCAM-1, E-selectin, and the chemokine MCP-1 in atherosclerotic tissue ex vivo and in human coronary artery and umbilical vein endothelial cells in an IL-1, MEK- and PI3K-independent but ST2- and NF-�B– dependent manner in vitro. Given the fact that the expression of ICAM-1, VCAM-1, E-selectin, and MCP-1 in atherosclerotic lesions has been reported to increase during atherogenesis and that this expression seems to be directly associated with plaque progression, 2,3,10,11 we hypothesize that IL-33, by promoting adhesion molecules and proinflammatory cytokine expression in the endothelium as well as adhesion of blood cells to the endothelium, may contribute to early events in endothelial dysfunction characteristic for the development of atherosclerotic lesions in the vessel wall. Downloaded from http://atvb.ahajournals.org/ at Bibliothek der MedUniWien (IX0000096057) on September 2, 2011
2088 Arterioscler Thromb Vasc Biol September 2011 Sources of Funding This work was supported by a grant from the Austrian Science Fund to Svitlana Demyanets (FWF-Project number T445-B11) and to Akos Heinemann (P22521-B18), by the Start Funding Program of the Medical University of Graz to Viktoria Konya (ASO109000101). Furthermore, the work was supported by the Association for the Promotion of Research in Arteriosclerosis, Thrombosis and Vascular Biology. None. Disclosures References 1. Braunwald E. Shattuck lecture–cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med. 1997; 337:1360–1369. 2. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340:115–126. 3. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874. 4. Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. 2010;30: 1282–1292. 5. Wagner DD, Frenette PS. 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