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Blood, 1 February 2004, Vol. 103, No. 3, pp. 754-755. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mallat, Z. Articles by Tedgui, A. Search for Related Content PubMed Articles by Mallat, Z. Articles by Tedgui, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NF-B activation in atherosclerosis: a friend or a foe? Atherosclerosis is an inflammatory disease of the arterial wall that carries an important socioeconomic burden. The severe clinical manifestations of atherosclerosis (myocardial infarction, stroke) are mainly due to the abrupt obstruction of the vessel lumen by a thrombus formed on the contact of a ruptured or eroded atherosclerotic plaque. The available data strongly suggest that immunoinflammatory–related mechanisms are the major determinants of plaque complications. Therefore, most of the important advances in the comprehension of the mechanisms of atherosclerosis have come from studies aimed at elucidating the critical components involved in the modulation of the immunoinflammatory balance within the plaque. However, despite the increasing knowledge regarding the role of inflammation in atherogenesis, the precise intracellular transduction pathways involved in this process remain largely unexplored. Recent studies have pointed to the transcription factor nuclear factor B (NF-B) as potentially one of the most important proinflammatory pathways in atherogenesis. Various risk factors for atherosclerosis, including hypercholesterolemia, diabetes and its associated advanced glycation end products, hypertension, elevated plasma homocysteine levels, and increased oxidative stress, which is common to all the preceding conditions, are important activators of NF-B. Activated NF-B has been identified in smooth muscle cells, macrophages, and endothelial cells of human atherosclerotic lesions,1 and enhanced activation of this transcription factor has been shown to occur very early following a high-fat, cholatefree diet in low-density lipoprotein receptor (LDLR)–deficient mice.2 However, apart from significant positive correlations between activated NF-B and proatherogenic activity, the direct role of NF-B in the development and composition of atherosclerotic plaques had not yet been assessed. In a recent study, Kanters et al, using LDLR-deficient mice with a macrophage-restricted deletion of IB kinase 2 (IKK2) leading to specific inhibition of NF-B activation in macrophages, reported the unexpected finding of increased atherosclerotic lesion formation and inflammation.3 This result was associated with a significant reduction in the anti-inflammatory and antiatherogenic cytokine interleukin-10 (IL-10), suggesting that a certain level of NF-B activation was required for the control of the inflammatory reaction and the protection against unabated inflammatory and proatherogenic responses. This is in agreement with studies showing a central role for NF-B in the induction of "protective" anti-apoptotic and anti-inflammatory genes, critical to the resolution of the inflammatory process.4 However, according to the study by Kanters and colleagues in this issue of Blood (page 934), the detrimental effect of NF-B inhibition in atherogenesis depends on how NF-B activity is inhibited. In this study, Kanters et al examined the effects of hematopoietic NF-B1 (p50) deficiency in the development of atherosclerotic lesions in LDLR knockout mice. Instead of promoting the formation of larger inflammatory lesions, as was the case with IKK2 deficiency, a significant decrease in lesion size in mice with NF-B1 deficiency, despite enhanced accumulation of T and B lymphocytes within the lesions, was observed. This could be explained, at least in part, by the observation that, in contrast to IKK2 deficiency, NF-B1 deficiency did not lead to an alteration of the inflammatory balance in favor of a proatherogenic phenotype. Despite increased tumor necrosis factor (TNF) expression by NF-B1–/– macrophages, other major proatherogenic molecules such as monocyte chemoattractant protein-1 (MCP-1) were down-regulated, whereas critical antiatherogenic factors such as IL-10 were significantly up-regulated. Decreased MCP-1 production and increased IL-10 expression may have contributed to limitation of plaque size despite enhanced accumulation of T cells. Another plausible mechanism leading to inhibition of lesion development in NF-B1–deficient animals could be attributed to a potential defect in the uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, as characteristic foam cells were absent in NF-B1–/– lesions and both scavenger receptor class A (SR-A) expression and uptake of oxLDL were significantly reduced in NF-B1–/– macrophages upon ex vivo stimulation with lipopolysaccharide (LPS). Whether this in vitro effect, observed following LPS stimulation, is relevant to the in vivo situation remains to be determined. NF-B appears to be at the crossroads of the inflammatory response in atherosclerosis, fine-tuning the response of the vessel wall to injury. Kanters et al should be commended for these provocative studies on the role of NF-B, one of the most important proinflammatory transcription factors, in atherosclerosis. Ziad Mallat, and Alain Tedgui Hôpital Lariboisière, Paris References Brand K, Page S, Rogler G, et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 1996; 97: 1715-1722.[Medline] [Order article via Infotrieve] Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A. 2000;97: 9052-9057.[Abstract/Free Full Text] Kanters E, Pasparakis M, Gijbels MJ, et al. Inhibition of NF-kappaB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;112: 1176-1185.[CrossRef][Medline] [Order article via Infotrieve] Lawrence T, Gilroy DW, Colville-Nash PR, Willoughby DA. Possible new role for NF-kappaB in the resolution of inflammation. Nat Med. 2001;7: 1291-1297.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Hematopoietic NF-B1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype Edwin Kanters, Marion J.J. Gijbels, Ingeborg van der Made, Monique N. Vergouwe, Peter Heeringa, Georg Kraal, Marten H. Hofker, and Menno P. J. de Winther Blood 2004 103: 934-940. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mallat, Z. Articles by Tedgui, A. Search for Related Content PubMed Articles by Mallat, Z. Articles by Tedgui, A. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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