Nickel and cobalt activate complement factor C3 faster than magnesium

We have found that incubation of heparin plasma with Ni(2+) or Co(2+) at concentrations below 100 microM can stimulate the conversion of complement factor C3 to C3b faster than magnesium, which is the natural cofactor in the alternative complement activation. This conversion was monitored by light absorbance measurement after separation by isotachophoresis, immunofixation and protein staining. The generation of C3b stimulated by these metals (<0.5 mM) proceeds up to about four times faster than the stimulation by Mg(2+). Half of total C3 in the incubation media was converted by Ni(2+) or Co(2+) at 0.5 mM after 20 min at 37 degrees C. Increasing Ni(2+) concentrations over 0.5 mM decreased the C3 conversion rate. Activation of C3 stimulated by Ni(2+), Co(2+) and Mg(2+) was concomitant with the conversion of complement factor B to Bb, but complement factor C4 was not affected by the activation. The conversion of B to Bb was monitored after separation by isotachophoresis and immunoblotting. Other divalent metal ions tested, namely Ca(2+), Ba(2+), Cu(2+) and Zn(2+), did not stimulate the complement cascade. We postulate that the increased rate of C3-fragment production induced by nickel or cobalt ions is central for the immunotoxicity of these metals.