The Effect of a Metalloproteinase Inhibitor (GI5402) on Tumor Necrosis Factor- (TNF-) and TNF- Receptors During Human Endotoxemia

Abstract

Tumor necrosis factor- (TNF-) is released from the cell surface by cleavage of pro–TNF- by metalloproteinases (MPs). In cell cultures, inhibition of MPs has been found not only to reduce the release of TNF-, but also to enhance the surface expression of TNF- and TNF- receptors, which might lead to a proinflammatory effect. To determine the effect of MP inhibition during inflammation in humans, 7 healthy subjects were studied after intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) preceded (−20 minutes) by an oral dose of the MP inhibitor GI5402 (100 mg) or matching placebo. GI5402 strongly reduced LPS-induced TNF- release (P < .001), but did not influence the increase in monocyte-bound TNF-. In addition, GI5402 attenuated the rise in plasma-soluble TNF- receptors types I and II after LPS injection (both P < .001), but did not change the LPS-induced decreases in granulocyte and monocyte TNF- receptor expression. These data suggest that MP inhibitors may be useful as a treatment modality in diseases in which excessive production of TNF- is considered to play an important role. Furthermore, unlike in vitro, no evidence has been found in vivo with MP inhibition for a potential proinflammatory effect due to increases in membrane-bound TNF- and TNF- receptor number.