Mechanism of regulation of complement receptor type 1 transcription by cytosine arabinoside in a pre-erythroid model

Binding to erythrocyte complement receptor type 1 (CR1) clears immune compl exes from blood and tissues, preventing complement-mediated pathological in flammation in disease. Previous work has demonstrated that Ara-C, a cytosin e analogue, induces an 11-fold increase in CR1 mRNA expression in K-562 ery throleukaemia cells. In this work we therefore investigated whether the Ara -C/K-562 system could be used as a model for studying the pre-erythroid reg ulation of CR1. We demonstrated that increased CR1 expression could be indu ced independently of increased haemoglobin expression. Increases in CR1 mRN A levels produced by Ara-C treatment were not a function of increased stabi lity of the message. However, Ara-C induced a protein synthesis-dependent i ncrease in transcription initiation rate as early as 12 h after treatment. Further data suggest that the effect of Ara-C on transcription is not a res ult of its direct DNA-damaging or DNA polymerase-inhibition activities. Ind uction of receptor transcription was inhibited by tyrosine kinase (TK) and protein kinase C (PKC) inhibitors. These data suggest that TK, PKC and dCTP -adducted phospholipid signalling pathways may all play a role in the mecha nism of Ara-C-induced CR1 transcription.