Recombinant IFN-gamma synergizes with lipopolysaccharide to induce macrophage membrane procoagulants.
Fibrin deposition is an important histopathologic feature of inflammation and is mediated, in part, by monocyte/macrophage procoagulants. rIFN gamma acted in synergy with suboptimal levels of bacterial LPS by priming thioglycollate-induced mouse peritoneal exudate cells (TG-PEC) to express high levels of surface procoagulant. TFN-alpha beta, TFN-alpha, IL-1, either alone or in combination with LPS or IFN-gamma, had no effect on macrophage procoagulant activity expression. In contrast to the dramatic increases of macrophage procoagulant activity induced by IFN-gamma/LPS, on exudate macrophages, normal peritoneal macrophages, or peripheral blood monocytes were unresponsive suggesting that the state of activation of the macrophage determines reactivity. IFN-gamma induced a Factor VIIa-like activity detected only after cell disruption. Synergy between LPS and IFN-gamma-induced procoagulants may occur as the result of the assembly of the thromboplastin (induced by LPS), Factor VII/VIIa complex on the macrophage surface. RNA synthesis was required for procoagulant induction. Procoagulant expression may, as for other cytokines involved in inflammatory responses, be regulated by short lived repressor proteins as low dose cycloheximide superinduced procoagulant responses to both LPS and IFN-gamma and caused the extracellular expression of procoagulant in response to IFN-gamma. This study suggests an important role for IFN-gamma in the assembly of components of the extrinsic coagulant cascade on the macrophage surface. The synergy between IFN-gamma and LPS may moderate macrophage-initiated fibrin deposition characteristic of inflammatory responses.
Moon
D K
DK
Kolling Institute of Medical Research, St. Leonards, N.S.W., Australia.
Geczy
C L
CL
D000818:Animals; D001779:Blood Coagulation Factors / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D001780:Blood Coagulation Tests; D004357:Drug Synergism; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology*
D001779:Blood Coagulation Factors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011500:Protein Synthesis Inhibitors; D011994:Recombinant Proteins; C045072:macrophage procoagulant activity; D012313:RNA; D007371:Interferon-gamma