Tumour-derived interleukin 1α (IL-1α) up-regulates the release of soluble intercellular adhesion molecule-1 (sICAM-1) by endothelial cells

Abstract

Summary Levels of circulating soluble intercellular adhesion molecule-1 (sICAM-1) are elevated in patients affected by solid malignancies; however, the cellular sources generating high levels of sICAM-1 remain to be characterized. Using conditioned media (CM) from seven ICAM-1-positive or -negative neoplastic cells, we demonstrate that tumour-derived interleukin 1a (IL-1 a) significantly (P < 0.05) up-regulates the release of sICAM-1 by human umbilical vein endothelial cells. The intensity of the effect correlated with the amounts of IL-la detectable in CM. Levels of ICAM-1 mRNA were also up-regulated by tumour-secreted IL-i a. The up-regulation of the shedding of sICAM-1 and of its expression at protein and mRNA level were completely reversed by the addition of anti-IL-i a neutralizing antibodies. Consistent with the in vitro data, tumour endothelia were strongly stained for ICAM-1 compared with autologous normal tissue endothelia. Taken altogether, our observations reveal an IL-la-mediated tumour-endothelium relationship sustaining the shedding of sICAM-1 by endothelial cells. This is a general phenomenon in solid malignancies that correlates with the ability of neoplastic cells to secrete IL-1a rather than with their expression of ICAM-1 and/or histological origin. sICAM-1 has been previously shown to inhibit LFA-1/ICAM-1-mediated cell-cell interactions; therefore, the ability of neoplastic cells to secrete IL-1a is likely to represent a mechanism for their escape from immune interaction.

Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicity

“…ICAM-1 shedding in MDA-MB435 cells transfected with MMP-9 is associated with resistance to NK cell-mediated cytotoxicity Several studies have shown that sICAM-1 released in the culture medium by cell lines can inhibit the cytotoxic effect of NK and LAK cells (Altomonte et al, 1993;Becker and Brocker, 1995;Becker et al, 1991;Fonsatti et al, 1997;Sanchez-Rovira et al, 1998). To address the effect of MMP-9 in promoting tumor cell resistance to NK-mediated cytotoxicity, we selected the breast cancer cell line MDA-MB435, which expresses mICAM-1, but no MMP-9 and no detectable sICAM-1 in cell culture supernatants.…”

“…However, ICAM-1 is shed from the surface of tumor cells, and serum levels of soluble ICAM-1 have even been proposed to provide an indicator of tumor burden (Grothey et al, 1998;Harning et al, 1991;Pizzolo et al, 1993). More to the point, shedding of ICAM-1 has been observed to inhibit cell mediated cytotoxicity and provide primary tumor cells as well as tumor cell lines with a mechanism of defense against cytolytic T cells and NK cells (Altomonte et al, 1993;Becker and Brocker, 1995;Becker et al, 1991;Fonsatti et al, 1997;Sanchez-Rovira et al, 1998). Recently, ICAM-1 release from the cell surface has been attributed to MMP activity (Lyons and Benveniste, 1998).…”

Rho GTPases and Leukocyte Adhesion Receptor Expression and Function in Endothelial Cells

“…In ECs, this is induced by cytokines and can be caused by MMP9 or the leukocyte elastase. [133][134][135][136] Soluble ICAM-1 may modulate leukocyte adhesion and migration by interacting with ␤2 integrins on the leukocyte surface, 38,137 but whether ICAM-1 shedding affects ICAM-1 signaling through its intracellular tail remains unclear.…”

ICAM-1: Contribution to Vascular Inflammation and Early Atherosclerosis

“…Alternative splicing has been suggested as one mechanistic pathway for the production of sICAM-1 (Wakatsuki, Kimura et al 1995). The inflammatory cytokines TNF-, IL-1 and IFN-have been reported to induce shedding of sICAM-1 from the cell surface of different primary cells and cell lines (Becker, Dummer et al 1991;Leeuwenberg, Smeets et al 1992;Pigott, Dillon et al 1992;Fonsatti, Altomonte et al 1997;Leung 1999). Furthermore, several proteases including matrix metalloproteases (MMP) (Lyons and Benveniste 1998); Tarín, Gomez, et al 2009), human leukocyte elastase (Champagne, Tremblay et al 1998) and TNF- converting enzyme (TACE) (Tsakadze, Sithu et al 2006) have been demonstrated to cleave sICAM-1 from the cell surface.…”