Dual response to Fas ligation in human endothelial cells: apoptosis and induction of chemokines, interleukin-8 and monocyte chemoattractant protein-1.

Abstract:

BACKGROUND:To maintain the integrity of tissues, endothelial cells play critical roles. Fas ligand (FasL) is well known to deliver a death signal through its receptor, Fas. The Fas/FasL system may concomitantly induce expressions of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) besides triggering apoptosis in endothelial cells. We also investigated whether an inhibitor of caspase-8 (Z-IETD-FMK) does modulate IL-8 and MCP-1 secretion. METHODS AND RESULTS:After treatment with interferon-gamma (IFN-gamma), human recombinant FasL (hr FasL) or Fas agonistic antibody (CH-11) was added to cultured human endothelial cells. IFN-gamma up-regulated Fas mRNA levels. Fas ligation promoted apoptosis assessed by fluorescent-activated cell sorter (FACS) analysis in a dose-dependent manner and induced prominent DNA fragmentation. Simultaneously, IL-8 and MCP-1 were secreted from the endothelial cells in response to hr FasL or CH-11 in a dose-dependent manner (P < 0.01). Fas-neutralizing agent (Fas-Fc) suppressed the Fas-mediated secretions of IL-8 and MCP-1 (P < 0.01) both as well as the Fas-mediated apoptosis. On the other hand, whereas Z-IETD-FMK suppressed apoptosis, the inhibitor enhanced the Fas-mediated secretions of both IL-8 and MCP-1 beyond the value of the Fas stimulation alone (P < 0.01), suggesting an enhanced signalling for the chemokine expression. CONCLUSION:In human endothelial cells, the Fas/FasL system induces both IL-8 and MCP-1 secretions probably via a caspase-8 independent pathway. The Fas/FasL system may amplify the inflammatory cascade in the vascular injury and atherogenesis by recruiting leukocytes at the region of apoptotic endothelial damage.

journal_name

Coron Artery Dis

journal_title

Coronary artery disease

authors

Yamaoka-Tojo M,Yamaguchi S,Nitobe J,Abe S,Inoue S,Nozaki N,Okuyama M,Sata M,Kubota I,Nakamura H,Tomoike H

doi

10.1097/00019501-200302000-00010

subject

Has Abstract

pub_date

2003-02-01 00:00:00

pages

89-94

issue

1

eissn

0954-6928

issn

1473-5830

journal_volume

14

pub_type

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