Interleukin-32 promotes lipid accumulation through inhibition of cholesterol efflux

Abstract

Abstract. Interleukin-32 (IL-32) is a pro-inflammatory cytokine and its effects in various inflammatory diseases have been investigated. However, the role of IL-32 on atherosclerosis, an inflammatory disease, remains unknown. The present study examined the use of IL-32α, the most abundant transcript of IL-32, in the treatment of oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages for 24 h, which simulates a foam cell formation model. The effect of IL-32α (20, 50 and 100 ng/ml) on lipid deposition in the macrophages was analyzed using Oil Red O staining, while the cholesterol efflux on apolipoprotein A-I was also measured. The mRNA and protein expression levels of peroxisome proliferator-activated receptor γ (PPARγ), liver X receptor α (LXRα), ATP-binding cassette transporter A1 (ABCA1) and ABCG1 were quantified by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The results indicated that IL-32α exposure enhanced the lipid deposition and attenuated the cholesterol efflux from ox-LDL-stimulated THP-1 macrophages in a dose-dependent manner. Furthermore, the expression levels of ABCA1, LXRα and PPARγ were dose-dependently decreased by IL-32α at the mRNA and protein levels. Addition of the PPARγ agonist 15d-PGJ2 or overexpression of PPARγ in THP-1 macrophages abrogated the IL-32α-mediated inhibition of cholesterol efflux and reversed the IL-32α-mediated downregulation of ABCA1 and LXRα. In conclusion, IL-32α enhances lipid accumulation and inhibits cholesterol efflux from ox-LDL-exposed THP-1 macrophages by regulating the PPARγ-LXRα-ABCA1 pathway.

Signaling Pathways and Key Genes Involved in Regulation of foam Cell Formation in Atherosclerosis

“…Nevertheless, it remains to be established whether the proinflammatory response can be considered as a trigger of foam cells formation [29]. A couple of recent papers report that the proinflammatory response is promoted by intracellular lipid accumulation [30,31].…”

“…Liu et al in 2018 demonstrated that IL-34 can act as a promotor of the lipid accumulation in bone marrow-derived macrophages through the up-regulation of CD36 expression [30]. Earlier, Xu et al showed that IL-32 stimulated lipid accumulation in THP-1 macrophages and inhibited the cholesterol efflux, thus facilitating foam cell formation [31]. In addition, our recent data indicate that inflammatory cytokines not only promoted the accumulation of intracellular cholesterol caused by modified LDL, but were also able to induce cholesterol accumulation in cultured primary macrophages (Table 2).…”

Possible Role of Mitochondrial DNA Mutations in Chronification of Inflammation: Focus on Atherosclerosis

“…Up-regulated phagocytosis, in turn, leads to the increased production of pro-inflammatory cytokines that attract monocytes and other immune cells to the emerging site of atherosclerotic lesion. Different research groups have shown that pro-inflammatory cytokines promote intracellular lipid accumulation induced by atherogenic modified LDL [33][34][35][36][37]. Moreover, in some cases, intracellular lipid accumulation is induced under inflammatory conditions even when modified LDL is not present [37].…”

Effects of ABCA1 gene polymorphisms on risk factors, susceptibility and severity of coronary artery disease

“…In vitro and in vivo studies disclosed that ABCA1 functions as an anti-inflammatory receptor and suppresses the expression of inflammatory factors such as interleukin-1beta, interleukin-6 and tumour necrosis factor-alpha and as an activator to stimulate the expression of anti-inflammatory factors such as IL-10 9 28. On the other hand, inflammatory factors also affect the expression of ABCA1 , for example, IL-32 has been shown to inhibit the expression of ABCA1 29…”