This remembrance was presented to the French Academy of Sciences by Professor Marcel Bessis' longtime colleague and friend, Professor Jean Bernard on January 30, 1995. It will be published in the original French in La Vie des Sciences, Vol. 10, No. 5, 1995. The editors are indebted to Dr. Malawista for making available to us the translation, so that this sensitive and moving presentation about the founder of our journal will more widely available.

ABSTRACT. Thrombosis and disseminated intravascular coagulation (DIC) are common complications of infections. Abnormal activation of coagulation is due in part to expression of tissue factor on intravascular cells in response to cytokines, including interleukin-1 beta (IL1á) and tumor necrosis factor (TNF). Both TNF and IL1á are thought to play significant roles in producing the pathologic manifestations of sepsis. Therefore, we examined the effects of thrombin on TNF and IL1á secretion by monocytes, and the ability of monocyte products to promote tissue factor expression by endothelial cells. Human monocytes were treated with thrombin or a thrombin receptor agonist peptide (SFLLRN), and/or bacterial lipopolysaccharide (LPS). The agonists were removed, and monocytes cultured 18 hours. The monocyte-conditioned supernatants were assayed for TNF and IL1á antigen, and for their ability to induce tissue factor expression on human umbilical vein endothelial cells and the Ea.hy endothelial cell line. Thrombin alone did not promote monocyte TNF or IL-1á secretion. However, thrombin enhanced LPS-induced TNF and IL1 secretion. Supernatants from monocytes exposed to LPS plus thrombin promoted greater tissue factor expression on endothelial cells than supernatants from those treated with LPS only. SFLLRN did not increase TNF secretion in response to LPS, but did enhance LPS-induced IL1á secretion and tissue factor-inducing activity. Neither SFLLRN nor active thrombin augmented the level of mRNA for TNF above that induced by LPS alone. However, both increased the LPS-induced level of IL1á message. Thus, thrombin enhanced LPS-induced TNF and IL1á secretion by monocytes. Unexpectedly, the effects on these two cytokines were mediated by different mechanisms. Enhancement of LPS-induced IL1á secretion was largely mediated via the tethered ligand type thrombin receptor and correlated with an increase in the steady state level of mRNA. By contrast, enhanced TNF required proteolytically active thrombin, but was not mediated by the tethered ligand receptor. These data demonstrate that physiologically relevant amounts of thrombin can synergize with endotoxin to stimulate monokine release. Thrombin could thereby play a role in the complex network of mediators involved in the pathophysiology of sepsis. We speculate that limiting thrombin activity during DIC could be a beneficial adjunct in the management of sepsis. Keywords: tumor necrosis factor, interleukin 1, blood coagulation, endotoxin, disseminated intravascular coagulation, thrombin receptor

Reprint requests to: Dr. Maureane R. Hoffman, Laboratory Service (113), Durham VA Medical Center, Durham, NC 27705.