Sublytic complement attack on oligodendrocytes (OLG) by activation of terminal complement complexes (TCC) selectively enhances the decay of myelin protein mRNAs. We have investigated whether TCC also stimulate differentiated OLG to enter the cell cycle and whether the cell cycle induction is related to the oncogene expression. Complement activation and TCC assembly induced expression of c-jun, JunD, and c-fos mRNAs, increased AP-1 DNA-binding activity within 1 h, and increased [3H]thymidine uptake. The c-jun NH2-terminal kinase activity was increased to the maximum level 20 min after TCC assembly. The increase in thymidine uptake was inhibited by pretreatment of OLG with antisense c-jun oligonucleotides. Studies on cyclin-dependent kinase (cdk) activation revealed that complement increased cyclin-dependent cell cycle associated kinase-2 activity in G1, while cdk2 and cdk4 showed low activity during G1 progression. However, the activity of cdk4 complexed with cyclin D2 showed a marked increase in G1/S transition. Our data provide evidence that sublytic TCC stimulate OLG to enter the cell cycle by induction of c-jun through activation of the c-jun NH2-terminal kinase pathway. In addition, sublytic TCC assembly significantly reduced the number of OLG undergoing apoptotic cell death, which occurs spontaneously in defined medium. These changes together with enhanced degradation of myelin protein mRNA may represent a mechanism for differentiated primary OLG to respond to limited complement activation in inflammation.