Characterization of the third component of complement (C3) after activation by cigarette smoke.
Activation of lung complement by tobacco smoke may be an important pathogenetic factor in the development of pulmonary emphysema in smokers. We previously showed that cigarette smoke can modify C3 and activate the alternative pathway of complement in vitro. However, the mechanism of C3 activation was not fully delineated in these earlier studies. In the present report, we show that smoke-treated C3 induces cleavage of the alternative pathway protein, Factor B, when added to serum containing Mg-EGTA. This effect of cigarette smoke is specific for C3 since smoke-treated C4, when added to Mg-EGTA-treated serum, fails to activate the alternative pathway and fails to induce Factor B cleavage. Smoke-modified C3 no longer binds significant amounts of [14C]methylamine (as does native C3), and relatively little [14C]methylamine is incorporated into its alpha-chain. Thus, prior internal thiolester bond cleavage appears to have occurred in C3 activated by cigarette smoke. Cigarette smoke components also induce formation of noncovalently associated, soluble C3 multimers, with a Mr ranging from 1 to 10 million. However, prior cleavage of the thiolester bond in C3 with methylamine prevents the subsequent formation of these smoke-induced aggregates. These data indicate that cigarette smoke activates the alternative pathway of complement by specifically modifying C3 and that these modifications include cleavage of the thiolester bond in C3 and formation of noncovalently linked C3 multimers.
D055598:Chemical Phenomena; D002621:Chemistry; D003167:Complement Activation; D003176:Complement C3 / Q000502:physiology*; D011415:Complement Factor B / Q000502:physiology; D003170:Complement Pathway, Alternative; D003545:Cysteine; D006801:Humans; D007460:Iodoacetamide; D008744:Methylamines; D008970:Molecular Weight; D010947:Plants, Toxic; D012906:Smoke; D014026:Nicotiana
D003176:Complement C3; D008744:Methylamines; D012906:Smoke; D011415:Complement Factor B; D003545:Cysteine; D007460:Iodoacetamide