Abstract
Despite aggressive dietary modification, lipid-lowering medications, and other interventional medical therapy, vascular disease continues to be a leading cause of mortality in the western world. It is a significant medical and socioeconomic problem contributing to mortality of multiple diseases including myocardial infarction, stroke, renal failure, and peripheral vascular disease. Morbidity and mortality of vascular disease are expected to worsen with the increasing number of patients with comorbid conditions such as obesity, metabolic syndrome, and diabetes mellitus type 2. Vascular diseases such as atherosclerosis, restenosis, and allograft vasculopathy are recognized to be driven by inflammation, and as such, cytokines which mediate inflammation not only represent important targets of rational therapy, but also can be considered as possible therapeutic modalities themselves. In this paper, we will examine the role of inflammatory cytokines and lymphocyte Th1/Th2 polarity in vascular inflammation, with a focus on atherosclerotic vascular disease. We will then introduce a recently described Th2 interleukin, interleukin-19 (IL-19), as a previously unrecognized mediator of vascular inflammatory disorders. We will review our current understanding of this interleukin in health and disease and present the possibility that IL-19 could represent a potential therapeutic to combat vascular inflammatory disease.
Highlights
Th1 and Th2 Interleukins in AtherosclerosisInterleukins are often classified according to their effects on lymphocyte function or maturation, as Th1 (proinflammatory, cytotoxic) which promotes inflammation, and Th2 (anti-inflammatory, antibody responses), which generally dampens inflammation [12]
Inflammation is a ubiquitous pathological process which is central to the development of multiple cardiovascular diseases
Many vascular diseases such as atherosclerosis, restenosis, and transplant vasculopathy are chronic, progressive processes initiated and propagated by local inflammation of large- and medium-sized arteries [1]. This inflammation is mediated by a variety of cell types including macrophage, lymphocyte, endothelial cell (EC), and vascular smooth muscle cell (VSMC)
Summary
Interleukins are often classified according to their effects on lymphocyte function or maturation, as Th1 (proinflammatory, cytotoxic) which promotes inflammation, and Th2 (anti-inflammatory, antibody responses), which generally dampens inflammation [12]. The prevailing hypothesis that atherosclerosis is a Th1 disease is supported by studies in which mice lacking IFN-γ or the IFN-γ receptor, TNF-α, or the Th1 transcription factor T-bet have reduced atherosclerosis [14,15,16] Further supporting this hypothesis, mice lacking STAT6, which is essential for Th2 cell differentiation, have increased atherosclerosis [17]. The mechanism is most likely mediated by inflammatory cells, as transfer of IL10−/− bone marrow to LDLR−/− polarizes the T lymphocyte Th2/Th1 ratio toward a more anti-inflammatory phenotype [19]. Considered to be a Th2 interleukin, IL-4 does not appear to be antiatherosclerotic, as IL-4−/− mice do not have increased atherosclerosis, and administration of IL-4 into ApoE−/− mice does not reduce development of atherosclerotic lesions [20]. Investigation of the role of Th2 cytokines as potential therapeutics in vascular inflammatory disorders, though understudied as it is, may be considered potentially promising as anti-inflammatory therapy for vascular disorders
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