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  • Cytokines are small secreted proteins that mediate and regul

    2021-06-16

    Cytokines are small secreted proteins that mediate and regulate immunity, inflammation, and hematopoiesis. They are produced in response to an immune stimulus. Cytokines regulate the intensity and duration of the immune response by stimulating or inhibiting the activation, proliferation, and/or differentiation of various cells and by regulating the secretion of endothelin receptor antagonists or other cytokines. Cytokines can be divided into 6 categories according to their function, including the interleukins (ILS), interferon (IFN), tumor necrosis factor (TNF) superfamily, colony stimulating factor (CSF), chemokines and growth factors (GF), and they play an important role in the regulation of proliferation, apoptosis, differentiation, inflammation and immunity. Among them, the apoptosis mediated by the inflammatory response is closely related to the occurrence and development of aortic dissection [4, 5, 8].
    The role of cytokines and AD
    ILs and AD At the second international symposium on lymphocytes in 1979, some non-specific factors secreted by monocytes/macrophages and lymphocytes that play a role in immune regulation and inflammation were uniformly named interleukins (ILs). So far, a total of 40 IL members have been discovered, named IL-1 to IL-40 in the order in which they were discovered [13]. According to biological function, ILs can be divided into the IL-1, IL-6, IL-10, IL-12, and IL-17 families. The IL-1 family is the general name for ILs that can bind to a group of related receptors, the receptor accessory protein (RAcP). As of now, 12 IL-1 family members have been found, including IL-1α, IL-1β, IL-1 receptor antagonist (RA), IL-18, IL-18 binding protein, IL-33, IL-36α, IL-36β, IL-36γ, IL-36RA, IL-37 and IL-38 [14]. In the pig AD model of suprarenal aortic cross-clamping, endothelin receptor antagonists IL-1β levels were increased [15]. In an earlier study, Zhang L et al. reported that IL-1β mRNA levels were increased in human type A thoracic AD and that IL-1β may participate in AD via up-regulation of matrix metalloproteinase-9 and apoptosis of media cells [16]. In another study, Cheuk BL. et al. found that circulating IL-1β levels were significantly decreased in patients who suffered from Stanford B AD and who received endovascular stents [17]. In an angiotensin II (Ang II)-induced mouse AD model, mercaptoethanol protected the aorta from dissection and reduced aortic IL-1β mRNA levels [18]. In addition, IL-1β mRNA levels increased in a time-dependent manner when AD formation was induced by b-aminopropionitrile monofumarate (BAPN) administration [19]. A recently published study reported that the IL-33/sST2 axis had some value in the diagnosis of AD [20]. No studies of other IL-1 family members and AD have been reported. The IL-2 family is also named the γ-chain (γc) family because the receptors for these cytokines share γc (also known as IL-2Rγ and CD132), which consists of IL-2, IL-4, IL-5, IL-7, IL-9, IL-15 and IL-21 [21]. Both circulating IL-2 and aortic IL-2 receptor are reported to increase in type A AD when compared with control subjects, and the IL-2 receptor negatively correlated with the follow-up period after repair [22, 23]. Our recent study showed that both circulating Th2/Th9 cells and their functional cytokines IL-4/IL-9 were reduced in human AD [24]. IL-5, IL-7, IL-15 and IL-21 were not reported to be involved in AD. Members of the IL-6 superfamily include IL-6, IL-11, IL-30, IL-31 and non-IL molecules, such as leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-2 (CT-2) and cardiotrophin-like cytokine (CLC) [25, 26]. The IL-6 family is characterized by their receptors, which share the GP130 subunit [26]. Data from clinical experiments and animal studies showed that both circulating and aortic IL-6 mRNA levels were elevated with AD [15, 17, 23, [27], [28], [29], [30]]. In addition, IL-6 could activate the signal transducer and activator of the transcription-3 pathway, promote Th17 infiltration of the aorta and enhance Ang II-induced AD in mice [31]. In another study, the authors found that IL-6 expression was significantly increased when compared to the controls and was accompanied by up-regulated autophagy in the human TAD aortic wall; down-regulation of IL-6 expression could repress expression of the VSMC contractile proteins α-SMA and SM22α via enhancement of autophagy-related 4B cysteine peptidase (ATG4B)-mediated autophagy in vitro [32]. In our recent study, we found that IL-11 was elevated in both plasma and the aortas of AD patients and that macrophages were the source of IL-11; this IL-11 may participate in AD via promotion of IFN-γ and IL-17 secretion [33]. Studies between other IL-11 members and AD have not yet been reported.