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Recombinant IFN-gamma synergizes with lipopolysaccharide to induce macrophage membrane procoagulants
Abstract:
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.
Insights
Interferon-gamma (IFN-γ) and lipopolysaccharide (LPS) synergize to boost macrophage procoagulant activity, a key factor in fibrin deposition during inflammation. This interaction highlights IFN-γ
Area of Science:
- Immunology
- Hematology
- Cell Biology
Background:
- Fibrin deposition is a hallmark of inflammation, involving monocyte/macrophage procoagulants.
- Understanding macrophage activation is crucial for inflammatory response modulation.
Purpose of the Study:
- To investigate the synergistic effect of interferon-gamma (IFN-γ) and lipopolysaccharide (LPS) on macrophage procoagulant activity.
- To explore the role of macrophage activation state in procoagulant expression.
Main Methods:
- Utilized thioglycollate-induced mouse peritoneal exudate cells (TG-PEC).
- Assessed procoagulant activity following stimulation with IFN-γ, LPS, and other cytokines.
- Investigated the requirement for RNA synthesis and the role of repressor proteins using cycloheximide.
Main Results:
- IFN-γ synergized with suboptimal LPS to significantly increase surface procoagulant expression on activated macrophages.
- Unstimulated macrophages and monocytes showed no response.
- IFN-γ induced a Factor VIIa-like activity, and synergy involved the assembly of thromboplastin and Factor VII/VIIa complex.
- RNA synthesis was essential, and repressor proteins regulated expression.
Conclusions:
- IFN-γ plays a critical role in assembling the extrinsic coagulant cascade on macrophage surfaces.
- The synergy between IFN-γ and LPS modulates macrophage-driven fibrin deposition in inflammation.