Cleavage of the Fifth Component of Complement and Generation of a Functionally Active C5b6-like Complex by Human Leukocyte Elastase

Abstract

Activation by complement C3/CS convertases of the fifth component of human complement, CS, leads to two active cleavage products: CSa, a chemotactic peptide, and CSb, the activated form of CS. Human leukocyte elastase (HLE) has long been known to also release from CS a chemotactic, CSa-like fragment. This, however, cannot be identical with CSa, since HLE does not cleave peptide bonds at the carboxyl group of arginine, the cleavage site that separates CSa and CSb after the exposure to the complement convertases. Therefore, the question arose whether HLE is capable of releasing a functionally CSb-like product from CS. The results show that this is, indeed, so. Treatment of human CS with HLE in the presence of C6 leads to the formation on an active C5b6-like complex that lyses non-sensitized guinea pig red cells upon addition of the terminal components C7, CS, and C9. However, since C6 is highly sensitive to the hydrolytic action of HLE, the yield of the activation complex is rather low. The results offer a third possibility for the activation of CS: 1) classical cleavage at Arg 74 by complement convertases, 2) oxidation of methionine residues without cleavage, and, as shown here, 3) cleavage by elastase at (a) site(s) distal from Arg 74 The three procedures may modulate the relative yield of the two activities generated from CS, CSa-like and CSb-like effects.