Abstract :
[en] Serine protease inhibitors (serpins) are a structurally related but functionally
diverse family of ubiquitous proteins. We previously described Ixodes ricinus
immunosuppressor (Iris) as a serpin from the saliva of the tick I. ricinus
displaying high affinity for human leukocyte elastase. Iris also displays
pleotropic effects because it interferes with both the immune response and
hemostasis of the host. It thus inhibits lymphocyte proliferation and the
secretion of interferon-gamma or tumor necrosis factor-alpha by peripheral blood
mononuclear cells, and also platelet adhesion, coagulation and fibrinolysis. Its
ability to interfere with coagulation and fibrinolysis, but not platelet
adhesion, depends on the integrity of its antiproteolytic reactive center loop
domain. Here, we dissect the mechanisms underlying the interaction of recombinant
Iris with peripheral blood mononuclear cells. We show that Iris binds to
monocytes/macrophages and inhibits their ability to secrete tumor necrosis
factor-alpha. Recombinant Iris also has a protective role in endotoxemic shock.
The anti-inflammatory ability of Iris does not depend on its antiprotease
activity. Moreover, we pinpoint the exosites involved in this activity.
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