The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin

Abstract

Summary Ancient organisms have a combined coagulation and immune system, and although links between inflammation and hemostasis exist in mammals, they are indirect and slower to act. Here we investigated direct links between mammalian immune and coagulation systems by examining cytokine proproteins for potential thrombin protease consensus sites. We found that interleukin (IL)-1α is directly activated by thrombin. Thrombin cleaved pro-IL-1α at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1α on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL-1α in the epidermis. Mice bearing a mutation in the IL-1α thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1α was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.

Thrombin: Coagulation's master regulator of innate immunity

“…Could the beneficial effects of these interventions with thrombin inhibitors be attributed, at least in part, to interference with thrombin‐mediated generation of IL‐1α? Aside from the preceding studies by Burzynski et al using models of skin wound healing and sepsis, little direct supportive evidence exists. However, preclinical and clinical studies render such a hypothesis reasonable, i.e.…”

“…In spite of early reports to the contrary, the current paradigm is that release of the C‐terminal cleavage product from pro‐IL‐1α is required for full biological activity . Therefore, delineating the mechanisms by which active IL‐1α is liberated from its pro‐form, is of potential therapeutic and diagnostic importance.…”

“…That Burzynski et al identified pro‐IL‐1α as a “new” substrate for thrombin raises the question as to whether there are other “hidden” but relevant targets for this potent enzyme. Thrombin is arguably one of the best‐characterized serine proteases .…”

“…In spite of early reports to the contrary, 16 the current paradigm is that release of the C-terminal cleavage product from pro-IL-1α is required for full biological activity. 17,18 Therefore, delineating the mechanisms by which active IL-1α is liberated from its pro-form, is of potential therapeutic and diagnostic importance. The value of such insights may be further augmented, if we consider that the concurrently released N-terminal pro-piece of pro-IL-1α may also be functionally relevant in health and disease.…”

“…The value of such insights may be further augmented, if we consider that the concurrently released N-terminal pro-piece of pro-IL-1α may also be functionally relevant in health and disease. 15 To this end, Burzynski et al 18 searched the pro-protein pro-IL-1α for potential protease consensus sites and identified a conserved (K)PRS sequence motif adjacent to the calpain cleavage site that was reminiscent of that for thrombin. Accessibility of this site to cleavage by the coagulationrelated enzyme was confirmed in a purified system, by rapid and efficient thrombin-mediated conversion of recombinant pro-IL-1α (p33 IL-1α) to mature IL-1α.…”