Disruption of the integrity of human peritoneal mesothelium by interleukin-1? and tumor necrosis factor-?

Abstract

Inflammatory and neoplastic disease processes of the abdominal cavity are frequently associated with disruption of the integrity of the peritoneal mesothelium. In the present study, we analyzed the effects of the pro-inflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on the morphology and expression of adhesion molecules of human peritoneal mesothelial cells (HPMC). Treatment of HPMC with IL-1beta and TNF-alpha resulted in a time- and dose-dependent alteration of the normal cobblestone morphology of the mesothelium with loss of polarization, cellular retraction and exposure of the submesothelial matrix. The effect was already observable after 6 h of treatment and was most pronounced at a dose of 10 ng/ml of IL-1beta or TNF-alpha. These morphological alterations were associated with a significant rearrangement of the expression of mesothelial adhesion molecules as detected by flow cytometry. IL-1beta and TNF-alpha both led to a loss of the expression of the hemidesmosomal integrin subunits alpha6 ( P<0.01 and P<0.001) and beta4 ( P<0.01) and an increased expression of the integrin subunit alpha5 ( P<0.001 and P<0.01). IL-1beta furthermore upregulated the expression of the integrin subunits alpha1, alpha2 and the adhesion molecule CD44 while the latter was downregulated by TNF-alpha. Our data indicate that IL-1beta and TNF-alpha may significantly affect disease processes of the abdominal cavity by their potential to disrupt the mesothelial basal cell-matrix adhesion and, thus, the integrity of the peritoneal mesothelial cell lining.

Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric matrix protein

“…CD61 might not be the only integrin that is down regulated by TNFa, because this also is seen for a6 and b4. 19 The b3 integrin subunit (CD61) forms a complex with the aV subunit (CD51) to form the vitronectin receptor. Our experimental data suggest that the aV and b3 integrins, independently of one another, or as a complex, are major switches regulating the attachment capability of these cells.…”

Tumor Necrosis Factor-α Differentially Modulates CD44 Expression in Ovarian Cancer Cells

“…Hyaluronic acid -rich peritoneal surface is the key metastatic site of ovarian cancer whose disruption may affect peritoneal tumor spread. TNF-a alters the morphology of the peritoneal mesothelium exposing the submesothelial matrix and it also down-regulates the expression of peritoneal CD44 (19). We have shown previously that CD44 in the ovarian cancer microenvironment, as determined by CD44 stromal expression, correlates with improved survival in ovarian cancer patients (16).…”

“…For example, CD44 is expressed in 86% of clear cell tumors of the ovary, one of the most aggressive histologic types, and is only expressed in 9% of endometrioid tumors that carry a better prognosis (15)(16)(17)(18). Our laboratory, as well as others, has evidence implicating CD44 and its interactions with the tumor stroma and the tumor microenvironment as relevant to ovarian cancer metastatic growth (16,19). In T cells, TNF-a affects cell migration by regulating CD44 expression through the activation of mitogen-activated protein kinases (MAPK).…”

Surgery promotes implantation of disseminated tumor cells, but does not increase growth of tumor cell clusters

“…Increased adhesion of tumor cells might represent one explanation since exposed ECM components as a result of mesothelial trauma has been shown to be a preferred site for adherence of tumor cells. In addition, inflammatory mediators produced after intraabdominal surgery were shown to disrupt the mesothelial monolayer with exposure of ECM, representing a preferential adhesion site as well [27,28]. Furthermore, following surgical trauma a local and systemic reactive inflammatory response is seen in order to initiate the wound healing process.…”