Leukaemia inhibitory factor enhances tissue factor expression in human monocyte-derived macrophages: a gp130-mediated mechanism

Leukaemia inhibitory factor (LIF) and interleukin (IL)-6 are members of a c ytokine group that share a common signal transducer gp130 and induce pleiot ropic biological effects in cells of diverse lineage. In monocytes, LIF fac ilitates differentiation, which may stimulate the biosynthesis of tissue fa ctor (TF) that initiates the coagulation cascade. We tested the hypothesis that LIF would enhance TF expression in human monocyte-derived macrophages (MDMs). Human peripheral blood mononuclear cells separated from whole blood by density centrifugation were allowed to differentiate into MDMs in prima ry culture, and were then exposed to LIF IL-6 and oncostatin M (OSM) for 24 h. LIF and IL-6 receptors, and gp130 were demonstrated in MDMs by immunocy tochemistry and RT-PCR. TF procoagulant activity (TF-PCA) was measured by r ecalcification clotting time and TF protein by Western blotting. The result s show that both TF procoagulant activity and TF protein increased signific antly in response to LIF over the concentration range of 1-100 nM (P<0.03). Although OSM and IL-6 tended to enhance TF expression by MDMs, the increas e did not reach statistical significance. Anti-LIF receptor and anti-gp130 antibodies attenuated the effect of LIF on TF expression as assayed by both bioassay and flow-cytometry. In conclusion, LIF increases TF-PCA and TF pr otein in MDMs, and specific anti-LIF receptor antibodies attenuate this eff ect. Thus, LIF may regulate by a gp130-dependent pathway macrophage-mediate d procoagulant function in diverse pathological states involving inflammati on and thrombosis and seems to serve as an important mediator at the interf ace between these processes.