MECHANISMS OF COMPLEMENT RESISTANCE INDUCED BY NONLETHAL COMPLEMENT ATTACK AND BY GROWTH ARREST

Non-lethal complement (C) attack on K562 cells has been shown to induc e a transient resistance to lethal amounts of C. We have previously sh own that incubation of K562 with phorbol 12-myristate 13-acetate (PMA) caused an increase in both CD59 expression and resistance to C killin g and we were interested to examine whether non-lethal C attack caused a similar effect. We here demonstrate that expression of the C inhibi tors decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 was unaltered on K562 after non-lethal C attack and that neut ralization of these inhibitors with specific blocking antibodies did n ot reverse the induced resistance. In an effort to understand the mech anisms of resistance we searched for other conditions that might induc e C resistance in K562 cells. Growth-arrested cells showed a similar d egree of resistance to C killing. The levels of DAF and MCP on these c ells were unaltered whereas expression of CD59 was markedly reduced. N on-lethal C attack on these growth-arrested cells induced a further in crease in resistance to C killing, suggesting that the mechanisms of r esistance were not identical. Indeed, resistance of non-lethally attac ked cells was completely lost within 8 hr of attack, whereas resistanc e of growth-arrested cells was detectable for up to 48 hr after return ing to cell cycle. These data demonstrate that C resistance induced by two distinct strategies is not mediated by the known membrane C inhib itors. Resistance may be a result of the expression of a novel inhibit or or due to metabolic depletion, a likely common consequence of non-l ethal C attack and induction of growth arrest, implying that cells tak e an active role in C-mediated killing.