RESUMO
BACKGROUND AND AIMS: The role of interleukin (IL-)32 in inflammatory conditions is well-established, however, the mechanism behind its role in atherosclerosis remains unexplained. Our group reported a promoter single nucleotide polymorphism in IL-32 associated with higher high-density lipoprotein (HDL) concentrations. We hypothesize that endogenous IL-32 in liver cells, a human monocytic cell line and carotid plaque tissue, can affect atherosclerosis by regulating (HDL) cholesterol homeostasis via expression of cholesterol transporters/mediators. METHODS: Human primary liver cells were stimulated with recombinant human (rh)TNFα and poly I:C to study the expression of IL-32 and mediators in cholesterol pathways. Additionally, IL-32 was overexpressed in HepG2 cells and overexpressed and silenced in THP-1â¯cells to study the direct effect of IL-32 on cholesterol transporters expression and function. RESULTS: Stimulation of human primary liver cells resulted in induction of IL-32α, IL-32ß and IL-32γ mRNA expression (pâ¯<â¯0.01). A strong correlation between the expression of IL-32γ and ABCA1, ABCG1, LXRα and apoA1 was observed (pâ¯<â¯0.01), and intracellular lipid concentrations were reduced in the presence of endogenous IL-32 (pâ¯<â¯0.05). Finally, IL32γ and ABCA1 mRNA expression was upregulated in carotid plaque tissue and when IL-32 was silenced in THP-1â¯cells, mRNA expression of ABCA1 was strongly reduced. CONCLUSIONS: Regulation of IL-32 in human primary liver cells, HepG2 and THP-1â¯cells strongly influences the mRNA expression of ABCA1, ABCG1, LXRα and apoA1 and affects intracellular lipid concentrations in the presence of endogenous IL-32. These data, for the first time, show an important role for IL32 in cholesterol homeostasis.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , HDL-Colesterol/metabolismo , Hepatócitos/metabolismo , Interleucinas/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Doenças das Artérias Carótidas/metabolismo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Homeostase , Humanos , Interleucinas/genética , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Poli I-C/farmacologia , Cultura Primária de Células , Células THP-1 , Fator de Necrose Tumoral alfa/farmacologia , Regulação para CimaRESUMO
Cardiovascular diseases (CVD) are the most frequent cause of death in developed countries. Their prevalence is higher in several chronic inflammatory conditions. This is likely due to the substantial contribution of the inflammatory status of the patients to the development and stability of atherosclerotic plaques. Recent evidence suggests that interleukin (IL)-32 may be involved in the conditions that contribute to CVD. IL-32 not only modulates important inflammatory pathways known to contribute to the pathogenesis of both inflammatory diseases and atherosclerosis, including tumor necrosis factor (TNF)α, IL-6 or IL-1ß, but it has been also suggested to modulate endothelial cell function and the serum concentration of high-density lipoprotein (HDL). In this review, we highlight the recent advances in the field of IL-32 in relation to chronic inflammatory disorders and argue for a role of IL-32 in the increased prevalence of CVD in these patients.