Interleukin-6 is a major regulator of lipoprotein(a) in humans in vivo
Aims: Lipoprotein (a) [Lp(a)] consists of an atherogenic LDL particle and pro-thrombotic apolipoprotein (a) [apo(a)] and has been considered as an independent cardiovascular risk factor. Recently, we have shown that inhibition of IL-6-signalling in humans in vivo lowers Lp(a) serum concentrations. Since there is currently no pharmaceutical agent available to reduce high Lp(a) levels, inhibition of IL-6 by neutralizing antibodies (e.g. tocilizumab) might be a future promising therapeutic option. Therefore, the effect of IL-6 on apo(a) was further examined on a molecular level.
Methodology: Human liver cells were used to investigate effects of IL-6 on apo(a) gene expression and promoter activity. IL-6 response elements (IL-6REs) present within the apo(a) promoter were examined by promoter deletion luciferase experiments and EMSA.
Results: IL-6-stimulation resulted in a significant increase of apo(a) but not of fatty-acid-synthase expression indicating specificity of this regulatory mechanism. Tocilizumab decreased IL6-induced apo(a) gene and protein expression. In contrast, TNF-α-antibody adalimumab did not decrease IL-6-induced apo(a) expression suggesting the effect of tocilizumab to be specific. Examination of IL-6REs within the apo(a) promoter showed specific IL-6-dependent STAT3 binding.
Conclusion: IL-6 is a major regulator of pro-atherogenic Lp(a) in humans in vivo. Therefore, IL-6 inhibition, e.g. by tocilizumab, is a promising future approach to lower Lp(a) in affected patients with high risk for cardiovascular events.