Granzyme B: A New Crossroad of Complement and Apoptosis
Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital of Ulm, Steinhoevelstr. 9, 89075 Ulm, Germany. Advances in Experimental Medicine and Biology
(Impact Factor: 1.96).
01/2012; 946:135-46. DOI: 10.1007/978-1-4614-0106-3_8
In response to severe tissue trauma, several "molecular danger" sensing and signaling pathways are activated, especially the complement and the apoptosis cascade. Although possible crossroads between both systems have been proposed, little is known about the underlying molecular interactions. In this study a new interaction interface is presented for C3a and C5a generation by the pro-apoptotic factor granzyme B. In vitro incubation of the central human complement components C3 and C5 with the serine protease granzyme B resulted in a concentration-dependent production of the anaphylatoxins C3a and C5a. The so generated anaphylatoxin C5a was chemotactic active for isolated human neutrophils. In a translational approach, intracellular granzyme B concentration in leukocytes was determined early after severe tissue trauma. In comparison to healthy volunteers, multiple injured patients (less than one hour after trauma, Injury Severity Score > 18, n = 5) presented a significant increase in granzmye B levels in neutrophils and lymphocytes. Thus, tissue trauma is associated with early activation of both, the complement and apoptosis system. The present data suggest a new form of interaction between the complement and the apoptosis system on the level of granzyme B that is capable to generate C3a and C5a independently of the established complement proteases.
Available from: Stephen M Taylor
- "The amplification cascade then culminates in the association of C5b with C6, C7 and C8, which induces the polymerisation of 10–16 C9 molecules in order to assemble a transmembrane pore called the terminal ‘membrane attack complex’ (MAC), with subsequent lysis of the targeted pathogens or abnormal host cells as a result . Importantly, components of the blood clotting and fibrinolysis pathways, as well as other cell-derived serine proteases, can also directly cleave and activate C3 and C5 proteins, and thus initiate the formation of complement end products, independent of the C3 and C5 convertases, a process that is now referred to as the extrinsic pathway[32-34]. "
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ABSTRACT: In response to severe tissue trauma several danger sensing and signalling cascades are activated, including the complement and the apoptosis systems. In polytrauma patients, both the early activation of the complement cascade with an excessive generation of the potent anaphylatoxin C5a and the induction of apoptosis have been shown to modulate the post-traumatic immune response. However, little is known about a direct interaction between the complement and apoptosis systems after severe tissue trauma. Therefore the focus of the present study was to elucidate the interplay between the central complement component C5 and the pro-apoptotic aspartic protease cathepsin D. In vivo, the cathepsin D plasma concentration of multiple injured patients was markedly increased when compared to healthy volunteers. In vitro incubation of C5 with cathepsin D resulted in a concentration- and time-dependent generation of C5a, which was inhibited by the aspartate protease inhibitor pepstatin A. Immunoblotting and sequencing analysis indicated that the C5 cleavage product represents the native form of human C5a, also exhibiting chemotactic activity for human neutrophils. In conclusion, these data show for the first time that cathepsin D is increased in plasma early after severe tissue injury. Furthermore, the results provide in vitro evidence of cleavage of C5 by an aspartic protease with subsequent generation of functional C5a, which represents a new path of complement activation.
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