Interleukin (IL)-33, a newly described member of the
IL-1 family, has been reported to facilitate primary
tumor progression and metastatic dissemination. However, its biological function on decidual stromal cells (DSCs) remains unclear. In this study, we tested the hypothesis whether
IL-33 promotes proliferation and invasion of DSCs, and the possible mechanism.
IL-33 and its orphan receptor ST2 was found to be co-expressed by DSCs in human first-trimester pregnancy. Addition of
IL-33, enhanced the proliferation and invasion of DSCs in a dosage-dependent manner, concomitantly with increasing expression of proliferation relative gene (
PCNA,
survivin) and invasion relative gene (
titin, MMP2). Blocking IL-33/ST2 signaling by soluble sST2 apparently abolished the stimulatory effect on the proliferation, invasiveness and related gene expression in DSCs. We also demonstrated that
chemokines CCL2/CCR2 was significantly increased with
IL-33 administration. Moreover, inhibition of CCL2/CCR2 activation using CCL2
neutralizing antibody or CCR2 blocker prevented IL-33-stimulated proliferation and invasiveness capacity of DSCs. Increasing phosphorylation of nuclear factor NF-κB p65 and
extracellular signal-regulated kinases ERK1/2
after treatment with
IL-33 was confirmed by western blotting. And the IL-33-induced CCL2/CCR2 expression was abrogated by treatment with the NF-κB inhibitor
BAY 11-7082 or ERK1/2 inhibitor
U0126. Finally, we showed that decreased IL-33/ST2 expression was observed in DSCs from
spontaneous abortion compared with normal pregnancy at both gene and
protein levels. This study provides evidence for the molecular mechanism of
IL-33 in promoting proliferation and invasiveness of DSCs by up-regulation of CCL2/CCR2 via NF-κB and ERK1/2 signal pathways and thus contributes insight to the potential of
IL-33 involved in successful pregnancy via inducing DSCs mitosis and invasion.