Enhanced adhesion of monocytes via reverse signaling triggered
by decoy receptor 3
Ming-Jen Hsu,
a,1
Wan-Wan Lin,
a,1
Wei-Chia Tsao,
a
Yung-Chi Chang,
b
Tsui-Ling Hsu,
b
Allen W. Chiu,
c
Chung-Ching Chio,
c
and Shie-Liang Hsieh
b,d,
*
a
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
b
Institute and Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
c
Department of Surgery, Chi-Mei Medical Center, Tainan, Taiwan
d
Immunology Research Center, National Yang-Ming University, Taipei, Taiwan
Received 15 May 2003, revised version received 28 August 2003
Abstract
Decoy receptor 3 (DcR3), a newly identified soluble protein belonging to the tumor necrosis factor receptor (TNFR) superfamily, is a
receptor for Fas ligand (FasL), LIGHT and TL1A. It has been demonstrated that DcR3 is frequently overexpressed by malignant tumors
arising from lung, gastrointestinal tract, neuronal glia and virus-associated leukemia. Recently, we demonstrated that DcR3 is able to
modulate the differentiation and activation of dendritic cells (DCs), and that DcR3-treated DCs skew naive T cell differentiation towards a
Th2 phenotype. In this study, we further demonstrate that DcR3 is able to induce actin reorganization and enhance the adhesion of monocytes
and THP-1 cells by activating multiple signaling molecules, such as protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), focal
adhesion kinase (FAK) and Src kinases. This provides the first evidence that the soluble DcR3, like other immobilized members of TNFR
superfamily, is able to trigger ‘reverse signaling’ to modulate cell function.
D 2003 Elsevier Inc. All rights reserved.
Keywords: DcR3; Monocyte adhesion; THP-1; Signal transduction; Reverse signaling
Introduction
Decoy receptor 3 (DcR3) is a decoy receptor belonging
to the tumor necrosis factor receptor (TNFR) superfamily
and contains the conserved cysteine-rich domains charac-
teristic of TNFR. Among the members of the TNFR
superfamily, DcR3 [1] and osteoprotegerin (OPG) [2] are
the only two receptors that lack transmembrane domain and
exist as soluble proteins. The DcR3 gene was reported to be
upregulated in cancers of gastrointestinal tract and pulmo-
nary origins [3], and DcR3 is also overexpressed in mela-
noma [4,5], autoimmune diseases [6] and virus-associated
leukemia [7]. Since DcR3 is able to interact with several
members of the TNF superfamily, such as Fas ligand (FasL)
[3,8], LIGHT [1,9] and TL1A [10], DcR3 is regarded as a
decoy receptor released by tumor cells to escape host
immune response by neutralizing the cytotoxic and immu-
nomodulatory effects of FasL, LIGHT and TL1A. Recently,
we further demonstrated that dimeric DcR3.Fc is able to
modulate CD14
+
monocyte differentiation into dendritic
cells (DCs) [11]. DcR3.Fc can downregulate the expression
of the MHC class II antigen HLA-DR, CD56/ICAM-1 and
CD80, while upregulating the expression of CD86. Incuba-
tion with DcR3.Fc-treated DCs skews naive T cell differen-
tiation towards a Th2 phenotype, while Fas.Fc (receptor for
FasL), LThR.Fc (receptor for LIGHT and lymphotoxin-
beta) and DR3.Fc (receptor for TL1A) have no effects on
0014-4827/$ - see front matter D 2003 Elsevier Inc. All rights reserved.
doi:10.1016/j.yexcr.2003.09.019
Abbreviations: ARTS-1, aminopeptidase regulator of TNFR1 shedding;
DCs, dendritic cells; DcR3, decoy receptor 3; FAK, focal adhesion kinase;
FasL, Fas ligand; IFN-g, interferon-gamma; LIGHT, homologous to LTs,
shows inducible expression and competes with HSV glycoprotein D for
herpesvirus entry mediator, a receptor expressed by T lymphocytes; LThR,
lymphotoxin h receptor; MAPK, mitogen-activated protein kinase; MEK,
mitogen-activated protein/ERK kinase; OPG, osteoprotegerin; PC-PLC,
phosphatidylcholine specific phospholipase C; PI3K, phosphatidylinositol
3-kinase; PI-PLC, phosphoinositide specific phospholipase C; PKC, protein
kinase C; TNFR, tumor necrosis factor receptor.
* Corresponding author. Institute of Microbiology and Immunology,
National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan. Fax:
+886-2-282-12880.
E-mail address: slhsieh@ym.edu.tw (S.-L. Hsieh).
1
Ming-Jen Hsu and Wan-Wan Lin have made equal contributions to
this work.
www.elsevier.com/locate/yexcr
Experimental Cell Research 292 (2004) 241– 251