Abstract-This review considers critically the evidence for the involvement of mediators of innate and acquired immunity in various stages of atherosclerosis. Rapidly mobilized arms of innate immunity, including phagocytic leukocytes, complement, and proinflammatory cytokines, contribute to atherogenesis. In addition, adaptive immunity, with its T cells, antibodies, and immunoregulatory cytokines, powerfully modulates disease activity and progression. Atherogenesis involves cross talk between and shared pathways involved in adaptive and innate immunity. Immune processes can influence the balance between cell proliferation and death, between synthetic and degradative processes, and between pro-and antithrombotic processes.

Background — Innate immune reactions against bacteria and viruses have been implicated in the pathogenesis of atherosclerosis. To explore the molecular mechanism by which microbe recognition occurs in the artery wall, we characterized the expression of toll-like receptors (TLRs), a family of pathogen pattern recognition receptors, in atherosclerotic lesions. Methods and Results — Semiquantitative polymerase chain reaction and immunohistochemical analysis demonstrated that of 9 TLRs, the expression of TLR1, TLR2, and TLR4 was markedly enhanced in human atherosclerotic plaques. A considerable proportion of TLR-expressing cells were also activated, as shown by the nuclear translocation of nuclear factor-κB. Conclusion — Our findings illustrate a repertoire of TLRs associated with inflammatory activation in human atherosclerotic lesions, and they encourage further exploration of innate immunity in the pathogenesis of atherosclerosis.

Nuclear factor kappa-B (NFkappaB), a redox-sensitive transcription factor regulating a battery of inflammatory genes, has been indicated to play a role in the development of numerous pathological states. Activation of NFkappaB induces gene programs leading to transcription of factors that promote inflammation, such as leukocyte adhesion molecules, cytokines, and chemokines, although some few substances with possible anti-inflammatory effects are also NFkappaB regulated. The present article reviews basic regulation of NFkappaB and its activation, cell biological effects of NFkappaB activation and the role of NFkappaB in apoptosis. Evidence involving NFkappaB as a key factor in the pathophysiology of ischemia-reperfusion injury and heart failure is discussed. Although activation of NFkappaB induces pro-inflammatory genes, it has lately been indicated that the transcription factor is involved in the signaling of endogenous myocardial protection evoked by ischemic preconditioning. A possible role of NFkappaB in the development of atherosclerosis and unstable coronary syndromes is discussed. Nuclear factor kappa-B may be a new therapeutic target for myocardial protection.

Leukotriene B4 (LTB4), a potent leukocyte chemoattractant derived from the 5-lipoxygenase metabolism of arachidonic acid, exerts its action by means of specific cell surface receptors, denoted BLT1 and BLT2. In this study, BLT1 receptor proteins were detected in human carotid artery atherosclerotic plaques, colocalizing with markers for macrophages, endothelial cells, and vascular smooth muscle cells (SMC). Challenge of human coronary artery SMC with either LTB 4 or U75302, a partial agonist that is selective for the BLT1 receptor, induced an Ϸ4-fold increase of whole-cell currents by using the patch-clamp technique, indicating that these cells express functional BLT1 receptors. LTB4 induced migration and proliferation of SMC in vitro, and treatment with the BLT receptor antagonist BIIL 284 (10 mg͞kg, once daily) for 14 days after carotid artery balloon injury in vivo inhibited intimal hyperplasia in rats. In the latter model, SMC derived from the intima exhibited increased levels of BLT 1 receptor mRNA compared with medial SMC. BLT receptor up-regulation in the intima in vivo, as well as that induced by IL-1␤ in vitro, were prevented by transfection with a dominantnegative form of I kinase ␤ carried by adenovirus, indicating that BLT1 receptor expression depends on NF-〉. These results show that LTB4 activates functional BLT1 receptors on vascular SMC, inducing chemotaxis and proliferation, and that BLT1 receptors were up-regulated through an I kinase ␤͞NF-B-dependent pathway. Inhibition of LTB4͞BLT1 signaling during the response to vascular injury reduced intimal hyperplasia, suggesting this pathway as a possible target for therapy.restenosis ͉ cell proliferation ͉ chemotaxis ͉ lipoxygenase ͉ eicosanoids L eukotrienes (LTs) are inflammatory mediators that are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism (1). Leukotrienes exert their actions by means of membrane-bound G protein-coupled receptors; CysLT receptors, which are activated by leukotrienes C 4 , D 4 , and E 4 ; and BLT receptors, which are activated by leukotriene B 4 (LTB 4 ) (2, 3). The last class consists of two receptor subtypes, BLT 1 and BLT 2 , representing the high-and low-affinity receptors for LTB 4 , respectively (4, 5). BLT receptors are expressed on leukocytes; neutrophils, eosinophils, and T lymphocytes all migrate in response to LTB 4 (6, 8-11).A major role for the leukotriene pathway in vascular disease was suggested by studies of a congenic mouse strain demonstrating resistance to atherosclerosis linked to a locus on chromosome 6, within which the gene for 5-LO was mapped subsequently (12). Also, expression of the enzymes and receptors of the 5-LO pathway has been demonstrated in human atherosclerotic plaques (13), and genetic studies have revealed that polymorphism in the 5-LO promoter is associated with an increased carotid artery intima thickness (14) and that the gene encoding the 5-LO-activating protein (FLAP) is associated with an increased risk of stroke and myocardial infarction (15).Although the...