17β-estradiol down-regulates lipopolysaccharide-induced MCP-1 production and cell migration in vascular smooth muscle cells

Abstract

Atherosclerosis is an inflammatory disease where lipopolysaccharide (LPS) triggers the release of inflammatory cytokines that accelerate its initiation and progression. Estrogen has been proven to be vasoprotective against atherosclerosis; however, the anti-inflammatory function of estrogen in the vascular system remains obscure. In this study, we investigated the effect of estrogen on LPS-induced monocyte chemoattractant protein-1 (MCP-1; listed as CCL2 in the MGI database) production in vascular smooth muscle cells (VSMCs). LPS significantly enhances MCP-1 production and this is dependent on nuclear factor k B (NFkB) signaling, since the use of NFkB inhibitor pyrrolidine dithiocarbamate or the silencing of NFkB subunit p65 expression with specific siRNA largely impairs LPS-enhanced MCP-1 production. On the contrary, 17b-estradiol (E 2 ) inhibits LPS-induced MCP-1 production in a time-and dosedependent manner, which is related to the suppression of p65 translocation to nucleus. Furthermore, p38 MAPK is rapidly activated in response to LPS, while E 2 markedly inhibits p38 MAPK activation. Transfection with p38 MAPK siRNA or the use of p38 MAPK inhibitor SB203580 markedly attenuates LPS-stimulated p65 translocation to nucleus and MCP-1 production, suggesting that E 2 suppresses NFkB signaling by the inactivation of p38 MAPK signaling. LPS promotes VSMCs migration and this is abrogated by MCP-1 antibody, implying that MCP-1 may play a major role as an autocrine factor in atherosclerosis. In addition, E 2 inhibits LPS-promoted cell migration by downregulation of MCP-1 production.Overall, our results demonstrate that E 2 exerts anti-inflammatory property antagonistic to LPS in VSMCs by reducing MCP-1 production, and this effect is related to the inhibition of p38 MAPK/NFkB cascade.

Testosterone: a vascular hormone in health and disease

“…Additionally, Nakagami et al (2010) have recently demonstrated that E 2 inhibits lipoprotein-a (an atherogenic lipoprotein)-induced expression of VCAM-1, ICAM-1 and E-selectin in bovine aortic endothelial cells and that IL1b, TNFa and MCP1 in macrophages differentiated from the THP-1 monocyte cell line. Indeed, E 2 inhibits MCP1 expression in rat thoracic aorta VSMCs (Jiang et al 2010) and inhibits human monocyte migration towards MCP1 in the culture, an effect that was abolished by ER blockade (Yamada et al 1996). The inhibition of monocyte migration was not demonstrated with testosterone treatment, suggesting that the ER effects are independent of testosterone conversion (Yamada et al 1996).…”

Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-κB pathways

“…LPS promotes inflammatory and immune responses via activation of almost all immune system cells, such as mac- rophages, mast cells, monocytes and VSMCs, which can cause over inflammation within atherosclerotic plaques. In VSMCs, LPS has been shown to induce the overexpression of many pro-inflammatory cytokines, including TNF-α, nitric oxide synthase, and MCP-1 [3,31,32] . Cur has been found to inhibit LPS-induced overexpression of vascular cell adhesion molecule-1 (VCAM-1), which plays a critical role in inflammatory responses within atherosclerotic plaques by regulating the [33] .…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…In addition, estrogens were demonstrated to reduce inflammatory activation of VSMC. For instance, the expression of COX2, MCP1, and endothelin 1 (ET1 (EDN1)) in response to serum, LPS, or Ang-II, respectively, was markedly attenuated in VSMC exposed to E 2 (Seli et al 2001, Hong et al 2004, Kawagoe et al 2007, Jiang et al 2010. Xing et al (2007) found that E 2 inhibits TNFa-stimulated expression of the neutrophil-specific chemokine cytokine-induced neutrophil chemoattractant (CINC)-2b and suggested that this effect might be responsible for the reduced infiltration of neutrophils, which is observed in animal models after vessel injury.…”