Gabexate Mesilate, a Synthetic Protease Inhibitor, Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of Both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

Abstract

Gabexate mesilate, a synthetic protease inhibitor, was shown to be effective in treating patients with sepsis-associated disseminated intravascular coagulation in which tumor necrosis factor-␣ (TNF-␣) plays a critical role. We demonstrated that gabexate mesilate reduced lipopolysaccharide (LPS)-induced tissue injury by inhibiting TNF-␣ production in rats. In the present study, we analyzed the mechanism(s) by which gabexate mesilate inhibits LPS-induced TNF-␣ production in human monocytes in vitro. Gabexate mesilate inhibited the production of TNF-␣ in monocytes stimulated with LPS. Gabexate mesilate inhibited both the binding of nuclear factor-B (NF-B) to target sites and the degradation of inhibitory B␣. Gabexate mesilate also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that gabexate mesilate inhibited LPS-induced TNF-␣ production in human monocytes by inhibiting activation of both NF-B and AP-1. Inhibition of TNF-␣ production by gabexate mesilate might explain at least partly its therapeutic effects in animals given LPS and those in patients with sepsis.

Activation of the Adenosine A3Receptor in RAW 264.7 Cells Inhibits Lipopolysaccharide-Stimulated Tumor Necrosis Factor-α Release by Reducing Calcium-Dependent Activation of Nuclear Factor-κB and Extracellular Signal-Regulated Kinase 1/2

“…There is indirect evidence that intracellular Ca 2ϩ is elevated in sepsis, which contributes to increased cellular injury (Song et al, 1993). Gabexate mesylate, a synthetic protease inhibitor, has proven effective in treating sepsis-associated symptoms, presumably by inhibiting the signaling pathways leading to TNF-␣ production (Yuksel et al, 2003). In animal models of septic shock, adenosine confers an anti-inflammatory action (Firestein et al, 1994), presumably by inhibiting similar pathways described for LPS.…”

The cytoprotective protein C pathway

“…For example, APC inhibits lipopolysaccharide (LPS)-induced production of proinflammatory mediators by monocytes. [49][50][51][52] Mechanisms for APC's anti-inflammatory effects on leukocytes are not completely clear; however, evidence indicates an important role for EPCR [38][39][40][41] that is on the surface of monocytes, CD56 ϩ natural killer cells, neutrophils, and eosinophils, but not T cells and B cells. 48,[53][54][55] Of interest, soluble EPCR lacking the transmembrane helix of native EPCR interacts with the integrin CD11b/ CD18 (Mac-1) (␣ M ␤ 2 ) (CR3) on leukocytes, suggesting that binding of soluble EPCR to CD11b/CD18 might interfere with leukocyte adhesion (Figure 2).…”

Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice

“…Data on antiinflammatory effects of aPC on leukocytes are largely derived from in vitro experiments on human immune cells, where EPCR expression has been reported in primary neutrophils (14), monocytes and macrophages (15)(16)(17), eosinophils (18), and NK cells (19). Such studies indicate that aPC, predominantly in an EPCR-dependent manner, modulates the inflammatory LPS response of mononuclear leukocytes, reduces leukocyte apoptosis, inhibits leukocyte responses to chemotactic signals (reviewed in refs.…”