Tumor necrosis factor/cachectin. Induction of hemorrhagic necrosis in normal tissue requires the fifth component of complement (C5).

Abstract

TNF induces hemorrhagic necrosis (HN) when injected into skin exposed to bacterial agents but not when injected into normal skin. In this paper, we present several lines of evidence suggesting that TNF requires the fifth component of complement (C5) to induce HN in skin exposed to bacteria. First, mouse strains that do not have C5 did not develop HN after injection of TNF and bacteria into skin. Second, plasma from C5-sufficient mice could correct the defect in these C5-deficient mice. Third, heating at 56 degrees C for 30 min inactivated the capacity of plasma to reconstitute C5-deficient mice. Fourth, CVF, which is known to inactivate complement, abrogated the capability of C5-sufficient mice to respond. Fifth, depleting plasma of hemolytic activity while generating C5a did not affect the capacity of the activated plasma to reconstitute C5-deficient mice. Finally, only the plasma fraction containing molecules of the size range of C5a reconstituted C5-deficient mice. These findings indicate that C5a and not the membrane attack complex is required for HN. Although we do not know through which mechanism C5a participates in the development of HN, we propose that the described HN response is related to a local defense mechanism in which TNF and C5a lead to the disruption of capillaries in the direct vicinity of bacteria. By this mechanism the rapid spread of bacteria or their products into the circulation is prevented. Such a tissue response is consistent with the known higher susceptibility of C5-deficient mice to bacterial infections and provides a model with which to search for the multiple steps involved in this important local defense mechanism.

Cytokines and their interactions with other inflammatory mediators in the pathogenesis of sepsis and septic shock

“…Sun & Hsueh [76] reported similar findings in rats. The concept that TNF by itself may be insufficient for vascular pathology is also supported by observations made by local injection in tissues, showing that haemorrhagic necrosis is dependent on the availability of C S [77].…”

Pharmacology and Biological Efficacy of a Recombinant, Humanized, Single-Chain Antibody C5 Complement Inhibitor in Patients Undergoing Coronary Artery Bypass Graft Surgery With Cardiopulmonary Bypass

“…[2][3][4] Finally, complement proteins can act synergistically with a number of cytokines in promoting inflammatory responses, as exemplified by the C5 dependence of tumor necrosis factor elaboration. 28,29 There is substantial preclinical evidence to support a critical role for complement in mediating inflammation and tissue injury associated with the CPB-induced inflammatory response. Ex vivo recirculation of whole blood in an extracorporeal closed-loop bypass circuit has been studied extensively as a model to reconstruct the bioincompatibility-induced complement and leukocyte activation that occurs during CPB.…”

Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

“…Thus, the antiinflammatory effect of C5 blockade in established arthritis could be due in part to inhibition of the activity of downstream inflammatory mediators. Evidence in support of this concept has come from studies demonstrating synergy between complement and TNF in several models of systemic inflammation (24)(25)(26)(27). It is possible that combined complement and cytokine inhibitor therapy of inflammatory disease could produce synergistic therapeutic efficacy.…”