Interleukin-6 Protects Human Macrophages from Cellular Cholesterol Accumulation and Attenuates the Proinflammatory Response

Frisdal, Éric; Lesnik, Philippe; Olivier, Maryline; Robillard, Paul; Chapman, M. John; Huby, Thierry; Guérin, Maryse; Goff, Wilfried Le

doi:10.1074/jbc.m111.264325

Cited by 101 publications

(79 citation statements)

References 56 publications

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“…IL-6 has been also demonstrated to increase the cholesterol efflux to HDL in macrophages. 10 Consequently, we hypothesized that IL-6 may modulate the transendothelial transport of HDL. Indeed, here we provide evidences that IL-6 enhances the binding and transport of HDL in an SR-BI-and ABCG1-independent way.…”

mentioning

confidence: 99%

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Robert

Lehner

Frank

et al. 2013

ATVB

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Objective-In the reverse cholesterol transport pathway, high-density lipoprotein (HDL) passes the endothelial cell barrier by mechanisms involving the scavenger receptor class B type I and the ATP-binding cassette G1. However, little is known on how inflammation influences this transendothelial transport. Approach and Results-On stimulation with interleukin-6, cultivated primary endothelial cells showed increased binding and transport of 125 I-HDL without changing the expression of scavenger receptor class B type I and ATP-binding cassette G1. Therefore, we analyzed the involvement of endothelial lipase (EL), a known HDL-binding protein expressed by endothelial cells. Here, we show an increased EL expression after interleukin-6 stimulation. Moreover, using pharmacological inhibitors or RNA interference against EL, we demonstrated its participation in HDL binding and transport through the endothelium. Furthermore, adenovirus-mediated transfection of endothelial cells with either catalytically active or nonactive EL revealed that EL facilitates the endothelial binding and transport by both bridging and lipolysis of HDL. EL was also found responsible for the reduction of HDL particle size occurring during the specific transport through a monolayer of endothelial cells. Finally, pharmacological inhibition of EL reversed the inducing effect of interleukin-6 on HDL binding and transport.Conclusions-Interleukin-6 stimulates the translocation of HDL through the endothelium, the first step in reverse cholesterol transport pathway, by enhancing EL expression. In addition, we demonstrated the role of EL in the transendothelial transport of HDL. [13][14][15][16] Moreover, several groups demonstrated the upregulation of EL on inflammatory stimulation both in vitro and in vivo. [17][18][19][20] In this study, we provide evidence that EL participates in endothelial binding, cell association, and transport of HDL. Materials and MethodsMaterials and Methods are available in the online-only Supplement. Results IL-6 Induces HDL Binding, Cell Association, and TransportTo investigate whether the interaction of HDL with endothelial cells is changed by the inflammatory cytokine IL-6, we stimulated aortic endothelial cells with IL-6. The interaction of HDL with the endothelial cells was characterized as binding at 4°C, cell association and transport at 37°C. IL-6 induced HDL binding to endothelial cells in a dose-and timedependent manner ( Figure IA and IB in the online-only Data Supplement). HDL binding was significantly increased after incubation with 1-or 10-ng/mL IL-6. Because of the maximal effects seen, all subsequent experiments were performed on cells that were stimulated without 0-or 10-ng/mL IL-6 for 24 hours. After 24 hours of IL-6 stimulation, specific binding was induced by 200±67% compared with not stimulated cells (100±28%; Figure 1A). Conversely, the specific cellularassociated HDL and the transported HDL were also increased by 144±21% and 178±39%, respectively, compared with not stimulated cells (100±17%; Figure 1B a...

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confidence: 99%

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Robert

Lehner

Frank

et al. 2013

ATVB

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“…IL-6 also maintains a separate anti-inflammatory and neuroprotective function through oligodendrocyte differentiation, neurotropism, and peripheral nerve regeneration mediated by the membrane-bound IL-6R on select cells such as microglia [26]. Human monocytes are directed away from differentiation into dendritic cells and toward macrophages which have increased anti-inflammatory IL-4 and IL-10 and decreased IL-1β production [27]. Given the dual roles of IL-6, it is possible the relative balance between the two pathways shifts with age.…”

Section: Discussionmentioning

confidence: 99%

Cytokine profiles in pediatric multiple sclerosis

Bhise

Balashov

Sturgill

et al. 2016

Mult Scler Demyelinating Disord

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Background: The immunopathogenesis of pediatric multiple sclerosis (MS) is not well understood. Methods: We studied the cytokine profile in pre-treatment serum specimens of 19 pediatric MS patients, 25 adult MS patients, and 22 age-and gender-matched pediatric healthy controls. In addition to IL-2, IL-12p40, IL-12p70, IL-18, IL-23, IL-6, TNF-α, TGF-β-1, IFN-γ, IL-17A, IL-21, IL-10, IL-4, IL-5, IL-13, and GM-CSF, we measured osteopontin and soluble VCAM-I. Results: In children with MS, significantly lower levels of IL-6 were present compared to age-and gender-matched healthy control children (p < 0.05). Moreover, significantly higher levels of osteopontin (p < 0.02) and sVCAM-1 (p < 0.02) and lower levels of IL-6 (p < 0.01) were present, with trends toward lower levels of IL-12p70 (p = 0.074) and IL-17a (p = 0.05) compared to adults with MS. Conclusions: These findings indicate important differences in cytokine signatures in children with MS and suggest an unexpected possible lower inflammatory cytokine profile in children with MS.

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“…In support of this idea, MFG-E8 [203] and its receptor v 3/5, as well as Gas6 and its ligand MerTK [116,204] are frequently overexpressed in breast cancers. One recent study demonstrated that the protumorigenic cytokine IL-6 induces expression of MerTK, enhancing the ability of macrophages to engulf apoptotic cells and increasing production of wound healing cytokines such as IL-4 and IL-10 [205]. Recently published data implicates MerTK in breast cancer metastasis [206].…”

Section: Physiological and Pathological Consequences Of Efferocytosismentioning

confidence: 99%

Apoptosis and Clearance of the Secretory Mammary Epithelium

Stanford¹,

Cook²

2013

Apoptosis

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Interleukin-6 Protects Human Macrophages from Cellular Cholesterol Accumulation and Attenuates the Proinflammatory Response

Cited by 101 publications

References 56 publications

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Interleukin 6 Stimulates Endothelial Binding and Transport of High-Density Lipoprotein Through Induction of Endothelial Lipase

Cytokine profiles in pediatric multiple sclerosis

Apoptosis and Clearance of the Secretory Mammary Epithelium

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