Monocyte killing of human squamous epithelial cells: role for thrombospondin

Human peripheral blood monocytes maintained in culture for 18 h were examined for killing of normal human keratinocytes and squamous carcinoma cells. Keratinocytes grown under conditions which maintain the undifferentiated state were highly sensitive to killing but these cells became resistant to killing after induction of differentiation. A line of squamous carcinoma cells obtained from an undifferentiated tumor (designated as UM-SCC-11B) was sensitive to killing while a second line obtained from a more well-differentiated tumor (designated as UM-SCC-22B) was resistant. Several observations suggested that interaction of monocytes with the squamous epithelial cells was mediated, in part, through thrombospondin (TSP). Monocytes synthesized TSP and were positive by immunofluorescence for surface TSP. The normal and malignant squamous epithelial cells also expressed surface TSP as well as unoccupied TSP receptors and our previous studies have shown that both TSP and its receptor are much more prominently displayed on the undifferentiated cells than on the differentiated cells. A series of anti-TSP monoclonal antibodies inhibited killing. These included an antibody directed against the Mr 25,000 NH2-terminal region of the molecule which has heparin-binding activity and three antibodies the epitopes of which lie within the Mr 140,000 non-heparin-binding fragment of TSP. High concentrations of exogenously added TSP as well as the recombinant form of the heparin-binding domain from the TSP molecule also partially inhibited killing while laminin and fibronectin were ineffective. Taken together, these data suggest that TSP and TSP receptors on monocytes and squamous epithelial cells play a role in monocyte-mediated killing of the squamous epithelial cells.