Innate Immunity in Coronary Disease. The Role of Interleukin-12 Cytokine Family in Atherosclerosis

Abstract

Atherosclerosis is a chronic, progressive, and multifactorial disease modulated by genetic and environmental factors. In recent years, the paradigm that explained atherosclerosis as resulting from a complex interaction between factors not accessible to medical intervention, and modifiable risk factors has changed. In this paradigm, alterations in lipid metabolism were the pivotal concept of atherosclerosis as a chronic degenerative disease. In the last years, an increasing number of observations have shown that the innate and adaptive immune responses to lipoprotein deposition and oxidation in the arterial wall significantly influence atherosclerosis. Currently, it is well recognized that the pathogenesis of atherosclerosis and its complications involves the inflammatory process, which includes the participation of several cytokines. Besides the classic cytokines involved in this process, the role of the interleukin-12 (IL-12) family has been recently demonstrated. This review describes our current understanding about the role of the family of IL-12 in atherosclerosis considering the participation of the genes that encode these cytokines in the genetic susceptibility to developing this disease.

Furin-responsive triterpenine-based liposomal complex enhances anticervical cancer therapy through size modulation

“…The determination of cytokines in the serum of tumor-bearing nude mice can reflect the antitumor mechanism of various tripterine treatments. It is well known that IFN-γ, IL-2, and IL-12A are capable of inhibiting tumor cell proliferation, blocking the angiogenesis pathway, regulating immunity, and decreasing the formation of tumor-associated fibroblasts (TAFs) (Mumm et al., 2011 ; Bunimovich-Mendrazitsky et al., 2016 ; Komohara et al., 2016 ; Yue et al., 2016 ; Jiang et al., 2017 ; Vourc’h et al., 2017 ; Wu et al., 2017 ; Ayuthaya et al., 2018 ; Burkart et al., 2018 ; Hydes et al., 2018 ; Kamensek et al., 2018 ; Lampreht Tratar et al., 2018 ; Posadassánchez & Vargasalarcón, 2018 ). In contrast, IL-10, IL-6, CCl2, TNF-α, and TGF-β are considered to be tumor-promoting cytokines, which could promote the proliferation of tumor cells, rebuilding of vascular networks, and so on (Alhamarneh et al., 2015 ; Song et al., 2015 ; Lau et al., 2016 ; Suchal et al., 2016 ; Kim et al., 2017 ; Kong et al., 2017 ).…”

A myriad of roles of dendritic cells in atherosclerosis

“…Predominantly expressed by macrophages and monocytes, IL-12 is also produced by DCs [6]. Recognized as a major regulator of adaptive type 1 cell-mediated immunity, this phagocyte-produced cytokine binds to naive CD4 + T cells and promotes the generation of proinflammatory Th1 cells, but antagonizes Th2 responses to have a negative impact upon T reg cells [76]. Significant expression of the IL-12 transcript and protein has already been identified in the atherosclerotic plaques of human samples [76].…”

“…Recognized as a major regulator of adaptive type 1 cell-mediated immunity, this phagocyte-produced cytokine binds to naive CD4 + T cells and promotes the generation of proinflammatory Th1 cells, but antagonizes Th2 responses to have a negative impact upon T reg cells [76]. Significant expression of the IL-12 transcript and protein has already been identified in the atherosclerotic plaques of human samples [76]. IL-12 was proved to be a proatherogenic molecule in ApoE −/− /IL-12 −/− mouse models due to the smaller size of atherosclerotic lesions in the absence of this cytokine than in its presence [77].…”

“…When in contact with T cells, DCs can secrete IL-12 family cytokines in large quantities, stimulate T cell proliferation, induce the generation of specific cytotoxic T lymphocytes (CTLs) for CD8 + T cells and dominate the Th1-type immune response for CD4 + T cells. The IL-12 family is evolutionarily associated with the IL-6 cytokine superfamily and composed of a single group of three possible α chains (p19, p28 or p35) and one of two β chains [p40 or Epstein-Barr virus-induced gene3 (EBI3)] [76]. In the early stage of atherosclerosis, the IL-12 cytokine family plays an important role in driving DCmediated differentiation of naive T cells [76].…”

Silencing IL12p35 Promotes Angiotensin II-Mediated Abdominal Aortic Aneurysm through Activating the STAT4 Pathway

“…The biological effect mediated by IL-12 is closely associated with signal transducer and activator of transcription (STAT) signaling, specifically STAT4 [15,16]. IL-12 has been identified as an important inflammationrelated cytokine involved in the regulation of several cardiovascular diseases, including myocardial infarction [17], atherosclerosis [18], and hypertension [19]. Recent studies have demonstrated that IL12p40 deficiency accelerates pathological matrix remodeling and promotes the development of AAA [20,21].…”