Induction of an angiogenic phenotype in endometriotic stromal cell cultures by interleukin-1 

Abstract

Activated peritoneal macrophages are associated with endometriosis and may play a central role in its aetiology by releasing interleukin-1beta (IL-1beta) in response to refluxed endometrium. Pari passu with the establishment of endometriotic implants is the development of a vascular supply. In this study we investigated the angiogenic properties of two endometrial proteins, vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6), and assessed their production in response to IL-1beta stimulation in human stromal cells isolated from normal endometrium (NE) and endometriotic lesions (EI). Proliferation of bovine brain capillary endothelial cells (BBCE) with a [(3)H]-thymidine incorporation assay was observed when VEGF (2.1 +/- 0.2-fold; P < 0.05) or VEGF and IL-6 (1.8 +/- 0.1-fold; P < 0.05) were added in vitro, relative to saline-treated control cultures. Northern blot analysis showed induction of VEGF mRNA (2.6-fold; P < 0.05) and IL-6 mRNA (6.3-fold; P < 0.05) transcripts in EI cells, but not NE cells, exposed to IL-1beta. A similar induction was seen with VEGF and IL-6 protein secretion in the responsive EI cells. Reverse transcription-polymerase chain reaction (RT-PCR) for the IL-1 receptor type I (IL-1 RI) indicated that the differential effects of IL-1beta on NE and EI cells was associated with 2.4 +/- 0.1-fold more receptor mRNA in EI versus NE cells. We propose that the ability of IL-1beta to activate an angiogenic phenotype in EI stromal cells but not in NE cells, is mediated by the IL-1 RI.

Increased expression of interleukin-1 receptor type 1 in active endometriotic lesions

“…In our previous studies, endometriotic cells showed a marked secretion of monocyte chemotactic protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), IL-6 and IL-8 following exposure to IL-1, and displayed a remarkable sensitivity for IL-1 (Akoum et al 1995(Akoum et al , 1996(Akoum et al , 2002. In keeping with our findings, data from Lebovic et al (2000) suggest that the ability of IL-1b to activate an angiogenic phenotype in endometriotic stromal cells, but not in stromal cells from normal endometrium, is mediated by the functional signaling receptor IL-1RI.…”

“…According to our and other previous studies, immune cells-derived cytokines, such as IL-1, may alone or in concert with estrogens, enhance the capability of ectopic endometrial cells to implant and develop into the host tissue, by inducing an angiogenic phenotype and stimulating the production of proinflammatory, growth, and tissue remodeling factors (Akoum et al 2000, 2002, Taylor et al 2002, Seli & Arici 2003, Wu & Ho 2003, Osteen et al 2004. Furthermore, our and other previous studies showed augmented sensitivity of endometriotic cells to the biological actions of IL-1 (Akoum et al 1995, 2002, Lebovic et al 2000, which may account for their ability to favor their own ectopic growth.…”

“…The inhibitory activity of IL-1ra was even shown to be enhanced by soluble IL-1RII and hindered by soluble IL-1RI (Burger et al 1995). According to our and other previous data, endometriotic cells are highly sensitive and responsive to IL-1 (Akoum et al 1995(Akoum et al , 2000(Akoum et al , 2002, and secrete increased levels of angiogenic factors compared with endometrial cells from normal women (Lebovic et al 2000). Also, IL-1RI is, in contrast to the decoy inhibitory IL-1RII, slightly released in the culture medium of endometrial and endometriotic cells (personal data).…”

“…IL-1 induces secretion of IL-8 and IL-6, which exhibit proangiogenic properties (Akoum et al 1996. Data from Lebovic et al (2000) showed an enhanced production of angiogenic molecules such as vascular endothelial growth factor (VEGF) and IL-6 in response to IL-1b in endometriotic cells, as compared with endometrial cells from normal endometrium, and increased expression of IL-1RI mRNA, suggesting a role for IL-1b ligand binding and signaling via IL-1RI. Therefore, in view of IL-1 biological effects, marked IL-1RI expression in active and early endometriosis lesions may play a significant role in promoting a successful implantation of endometrial tissue in the earliest steps of endometriosis following retrograde menstruation.…”

Significance of ovarian macrophages in the follicular aspirates from ART patients

“…VEGF is a highly mitogenic factor for vascular endothelial cells that also promotes cell migration and inhibits apoptosis [15]. Additionally, IL-1β and IL-6 have been shown to induce the expression of VEGF in different kind of cells [16][17][18].…”