Release of Interleukin-6 and Its Soluble Receptors by Activated Peripheral Blood Monocytes Is Elevated in Hypocholesterolemic Hemodialysis Patients

Abstract

Background: A reverse association between cholesterol level and cardiovascular disease mortality is observed in hemodialysis (HD) patients; this paradoxical relationship may be explained by the coexistence of inflammation. Interleukin-6 (IL-6) is a central regulator of inflammation; its action is augmented by the soluble IL-6 receptor (sIL-6R) and inhibited by the soluble gp130 (sgp130). In order to investigate the potential association of inflammation with cholesterol levels in the HD population, release of soluble IL-6 components by peripheral blood mononuclear cells (PBMCs) was measured in two groups of HD patients with distinctly different lipid profile and in a control group. Methods: Twenty-two HD patients with low serum cholesterol (range 85–171 mg/dl), 23 HD patients with high cholesterol (189–342 mg/dl) and 21 normolipidemic non-renal failure subjects were enrolled in the study. IL-6, sIL-6R and sgp130 were measured by ELISA in the serum and in the supernatant collected from cell cultures of activated or resting PBMCs isolated from all three groups. Results: Serum IL-6 and sgp130 level was higher while sIL-6R was lower in both groups of HD patients compared to the control group. The ex-vivo release of the IL-6 and sgp130 by unstimulated PBMCs did not differ significantly between the three groups but that of the sIL-6R was higher in non-renal failure than in hypercholesterolemic HD subjects. Production of sIL-6R by stimulated PBMCs was higher in low-cholesterol HD patients (p < 0.001) and the same was valid for the sgp130 release (p = 0.034). Release of IL-6 by activated PBMCs was higher in the low-cholesterol compared to the high-cholesterol HD patients group (p = 0.011 for post hoc test). Major serum lipid fractions were inversely correlated to IL-6 and sIL-6R production from stimulated PBMCs in HD but not in non-renal failure subjects. Finally, release of the sgp130 by PBMCs was significantly reduced in 13 hypertriglyceridemic – and hypercholesterolemic – HD patients. Conclusion: Production of soluble components of a crucial pro-inflammatory and potentially atherogenic cytokine, namely the IL-6, by stimulated PBMCs appears to be inversely correlated with the serum cholesterol levels in HD patients.

Low cholesterol along with inflammation predicts morbidity and mortality in hemodialysis patients

“…Interleukin‐6 alone, measured at baseline, and no other inflammation marker, was negatively correlated to the main lipid fractions. This finding supports our results in an ex vivo study where it was concluded that the release of IL‐6 and its soluble receptors by peripheral blood monocytes is elevated in hypocholesterolemic HD patients 15 . On the other hand, this negative correlation supports only partially the hypothesis that reverse epidemiology regarding cholesterol is observed only when inflammatory activity is high.…”

“…This finding supports our results in an ex vivo study where it was concluded that the release of IL-6 and its soluble receptors by peripheral blood monocytes is elevated in hypocholesterolemic HD patients. 15 On the other hand, this negative correlation supports only partially the hypothesis that reverse epidemiology regarding cholesterol is observed only when inflammatory activity is high. The other markers of inflammation were not negatively correlated to the lipid fractions.…”

Association of Serum Lipid Profile and Arteriovenous Fistula Thrombosis in Maintenance Hemodialysis Patients

“…Alterations in lipoprotein composition reduce defense mechanisms that would reduce the effects of inflammation on vascular structure in patients with renal failure [14] . Furthermore, some authors suggest that hypocholesterolemia is not simply associated, but may also be causally related to the production of soluble components of a pro-inflammatory and potentially atherogenic cytokine, interleukin-6, by the circulating monocyte [15] .…”

High habitual dietary α-linolenic acid intake is associated with decreased plasma soluble interleukin-6 receptor concentrations in male twins

“…IL-6R concentrations in humans' atherosclerotic plaques are positively associated with CVD risk factors, including smoking and diabetes (31). A paradoxically adverse relation between blood cholesterol concentrations and CVD mortality in hemodialysis patients has been attributed to less sIL-6R released from activated peripheral blood mononuclear cells (32). These previous findings primarily link sIL-6R to CVD risk in patient populations.…”