ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells

Abstract

ST2 gene products that are members of IL-1 receptor family are expressed in various cells such as growth-stimulated fibroblasts and Th2 helper T-cells, and recently, IL-33, which belongs to IL-1 family, was identified as the ligand for ST2L, the receptor type product of the ST2 gene. Subsequently, IL-33 and ST2L have been reported to be involved in Th2 immunity and inflammation, however, their functions on non-immunological cells are still obscure. Among non-immunological adhesive cells, vascular endothelial cells were reported to express both ST2 gene products and IL-33, therefore, we investigated the expression manner of the ST2 gene in vascular endothelial cells and the effect of IL-33 on endothelial cells. ST2 gene was expressed in each of the vascular endothelial cell types tested, and the expression was growth-dependent and down-regulated when the cells were differentiated to form vascular structures on the extracellular membrane matrix. IL-33 scarcely affected the growth and tube formation of the endothelial cells, but induced IL-6 and IL-8 secretion from endothelial cells with the rapid activation of extracellular signal-regulated kinase (ERK) 1/2, so IL-33 is supposed to involve in inflammatory reaction of vascular endothelial cells through its receptor, ST2L.

Interleukin-33 Induces Expression of Adhesion Molecules and Inflammatory Activation in Human Endothelial Cells and in Human Atherosclerotic Plaques

“…In agreement with a recently published study, we found that IL-33 also upregulated the inflammatory cytokines IL-6 and IL-8 in human endothelial cells. 31 In parallel with increased VCAM-1, ICAM-1, E-selectin, and MCP-1 protein production, IL-33 caused a marked upregulation of specific mRNA for VCAM-1, ICAM-1, E-selectin, and MCP-1 in human coronary artery and umbilical vein endothelial cells. The effect was specific for IL-33 because sST2-Fc but not IgG 1 -Fc abrogated these IL-33-induced effects in endothelial cells.…”

“…In agreement with published data, IL-6 and IL-8 protein production was also increased under IL-33 treatment in both endothelial cell types (data not shown). 31 Also in HCAEC, IL-33 treatment dose-dependently increased ICAM-1 ( Figure 2E), VCAM-1 ( Figure 2F), E-selectin ( Figure 2G), and MCP-1 protein ( Figure 2H) after 4 hours of incubation.…”

“…28,30 In human endothelial cells, however, IL-33 was shown to induce inflammatory activation as evidenced by increased vascular permeability, the increased production of inflammatory cytokines, and the stimulation of angiogenesis. 27,31 In this article, we provide evidence for yet another aspect of inflammatory activation of human endothelial cells by IL-33 by showing that this cytokine, which we found to be expressed in human atherosclerotic tissue, stimulates adhesion of leukocytes to the endothelium under both static and flow conditions and upregulates the expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin and of the chemokine MCP-1 in human endothelial cells in vitro. Furthermore, we demonstrate that the latter effects of IL-33 are also operative in explanted human atherosclerotic plaque tissue ex vivo.…”

Interleukin-33 plasma levels in patients with relapsing-remitting multiple sclerosis

“…The IL-33/ST2 pathway is pivotal to inflammatory responses and autoimmune disorders (23). It has been reported that ST2L is principal for the inflammatory activity of IL-33 because of expression on several immune cells like endothelial cells, mast cells, macrophages, basophiles and dendritic cells (18,19,(24)(25)(26)(27)(28).…”

The enigmatic processing and secretion of interleukin-33

“…14,27 IL-33 must be present extracellularly in order to play the crucial role in inflammatory, infectious and autoimmune diseases including anaphylactic shock, asthma, rheumatoid arthritis, atherosclerosis, systemic sclerosis and cardiovascular diseases. 5,11,[28][29][30][31][32][33][34][35][36][37][38] However, complexities and a number of discrepancies in the processing and secretion of IL-33 have been uncovered in the accumulated data. For example, full-length 31-kDa IL-33 1-270 has been reported, variously, as the immature/mature or inactive/active IL-33.…”