Inhibition of cleavage of the third component of human complement (C3) by its small cleavage fragment, C3a: inhibition occurs with the classical-pathway, but not the alternative-pathway, C3 convertase |
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Authors: | R C Strunk R O Webster |
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Affiliation: | 1. Department of Pediatrics, National Jewish Hospital and Research Center, and the University of Colorado School of Medicine, Denver, CO 80206, U.S.A.;2. Pulmonary Division, Department of Internal Medicine, St. Louis University Medical Center, St. Louis, MO 63104, U.S.A. |
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Abstract: | Activation of the third component of complement (C), C3, is central to the functioning of the C system in inflammation. Cleavage of C3 by the C3 convertases of both the classical and alternative pathways results in the formation of two split products, C3b and C3a. C3a inhibited cleavage of C3 by the classical-pathway C3 convertase. The inhibition varied in a concn-dependent relationship, with a concn of approximately 40 micrograms/ml yielding 50% inhibition. Removal of the carboxy terminal arginine from the C3a did not alter the inhibition. C3a did not inhibit cleavage of C3 by the alternative C pathway C3 convertase, or cleavage of C5 by C5 convertase. The C3-cleaving capacity of EAC142oxy that had been previously incubated with C3a could be recovered completely by washing the cells, indicating that the C3a binding to the EAC42oxy cell must have been reversed without having had an effect on the amount of C2 bound. Ribonuclease, a molecule of similar size and charge to C3a, did not affect C3 cleavage and C3a inhibition was not reduced by providing a surface for non-specific adsorption of the C3a, suggesting that the effect of C3a on C3 cleavage was not mediated by non-specific interaction with cell surfaces. C3a inhibited the C3-cleaving capacity of the fluid-phase enzyme, C42oxy, to the same degree as it inhibited the cell-bound enzyme, EAC42oxy, indicating that the C3a must interact with the C42 complex directly. Inhibition of C3 cleavage by C3a is the first demonstration of product inhibition of a complement enzyme. It may provide another control of C3 activation. |
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Keywords: | C1 the first component of complement (C) C2 the first component of complement (C) C3 the first component of complement (C) C5 the fifth component of complement (C) C3a 9000-dalton split product of C3 cleavage oxidized C2 RNase ribonuclease classical C pathway cell-bound C3 convertase classical C pathway fluid-phase C3 convertase ZC alternative-pathway surface-bound C3 convertase classical-pathway C5 convertase VBS-glucose veronal-buffered saline glucose |
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