Tài liệu Báo cáo khoa học: Liver X receptor agonists inhibit tissue factor expression in macrophages

Liver X receptor agonists inhibit tissue factor expression

in macrophages

Naoki Terasaka1

, Ayano Hiroshima1

, Akiko Ariga1

, Shoko Honzumi1

, Tadashi Koieyama1

,

Toshimori Inaba2 and Toshihiko Fujiwara1

1 Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan

2 Pharmacodynamics Research Laboratories, Sankyo Co. Ltd, Tokyo, Japan

Tissue factor (TF) is the cell surface glycoprotein that

functions as the major cellular initiator of the coagula￾tion protease cascades [1–4]. It is a high-affinity recep￾tor for serine protease factors VII and VIIa. The

resulting TF–factor VIIa complex provides the first

catalytic event which is responsible for initiation of the

coagulation protease cascades. TF-initiated thrombosis

is associated with many diseases, including Gram￾negative sepsis, cancer, and atherosclerosis [5–8].

Atherosclerosis is a chronic inflammatory disease

as well as a disorder of lipid metabolism [9–11]. As

modulators of both lipid metabolism and immune

responses, macrophages play a central role in the ath￾erogenic process. The accumulation of cholesterol￾loaded macrophages in the arterial wall is the hallmark

of early atherosclerotic lesions. TF plays an important

role in the pathogenesis of thrombus formation at sites

of atherosclerotic plaque disruption resulting in acute

Keywords

atherosclerosis; genes; lipopolysaccharide;

liver X receptor; macrophage; tissue factor

Correspondence

N. Terasaka, Pharmacology and Molecular

Biology Research Laboratories, Sankyo Co.,

Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo

140-8710, Japan

Fax: +81 3 5436 8566

Tel: +81 3 3492 3131

E-mail: [email protected]

(Received 5 November 2004, revised 17

January 2005, accepted 4 February 2005)

doi:10.1111/j.1742-4658.2005.04599.x

Exposure of blood to tissue factor (TF) rapidly initiates the coagulation

serine protease cascades. TF is expressed by macrophages and other types

of cell within atherosclerotic lesions and plays an important role in throm￾bus formation after plaque rupture. Macrophage TF expression is induced

by pro-inflammatory stimuli including lipopolysaccharide (LPS), inter￾leukin-1b and tumor necrosis factor-a. Here we demonstrate that activation

of liver X receptors (LXRs) LXRa and LXRb suppresses TF expression.

Treatment of mouse peritoneal macrophages with synthetic LXR agonist

T0901317 or GW3965 reduced TF expression induced by pro-inflammatory

stimuli. LXR agonists also suppressed TF expression and its activity

in human monocytes. Human and mouse TF promoters contain binding

sites for the transcription factors AP-1, NFjB, Egr-1 and Sp1, but no

LXR-binding sites could be found. Cotransfection assays with LXR and

TF promoter constructs in RAW 264.7 cells revealed that LXR agonists

suppressed LPS-induced TF promoter activity. Analysis of TF promoter

also showed that inhibition of TF promoter activity by LXR was at least

in part through inhibition of the NFjB signaling pathway. In addition,

in vivo, LXR agonists reduced TF expression within aortic lesions in an

atherosclerosis mouse model as well as in kidney and lung in mice stimula￾ted with LPS. These findings indicate that activation of LXR results in

reduction of TF expression, which may influence atherothrombosis in

patients with vascular disease.

Abbreviations

ABC, ATP-binding cassette; apoE, apolipoprotein E; COX, cyclo-oxygenase; DMEM, Dulbecco’s modified Eagle’s medium; Egr-1, early

growth response-1; IL, interleukin; iNOS, inducible nitric oxide synthase; KLF, Kru¨ppel-like factor; LDLR, low-density lipoprotein receptor;

LPS, lipopolysaccharide; LPDS, lipoprotein protein-deficient serum; LXR, liver X receptor; MMP, matrix metalloproteinase; NFjB, nuclear

factor-jB; PPAR, peroxisome proliferator-activated receptor; RAR, retinoic acid receptor; RXR, retinoid X receptor; TBST, Tween 20 Tris

buffered saline; TF, tissue factor; TNFa, tumor necrosis factor-a.

1546 FEBS Journal 272 (2005) 1546–1556 ª 2005 FEBS