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The protein zero (P0) glycoprotein is an important component of compact peripheral nerve myelin produced by the glial cells of the mammalian peripheral nervous system. P0 mRNA expression is reduced following exposure of Schwann cells to sublytic C5b-9, the terminal activation complex of the complement cascade. Sublytic complement treatment decreased P0 mRNA by 81% within 6 h and required C5b-9 assembly. C5b-9 induced a threefold increase in both JNK1 activity and c-jun mRNA within 20 and 30 min, respectively, compared with cells treated with either human serum depleted of complement component C7 (C7dHS) or medium alone. Sublytic C5b-9 stimulation, in the presence of the transcription inhibitor Actinomycin D, decreased P0 mRNA expression by 52%, indicating that mRNA was selectively destabilized. This effect was prevented by pretreatment with L-JNK inhibitor 1 (L-JNKI1). To study a potential inhibition of P0 gene transcription, we transfected Schwann cells with a P0 promoter-firefly luciferase construct. Sublytic C5b-9 stimulation of the transfected cells decreased luciferase activity by 82% at 6 h, and this effect was prevented by pretreatment with L-JNKI1 inhibitor. Our results indicate that the ability of C5b-9 in vitro to affect P0 gene expression is mediated via JNK1 activation that leads to enhanced mRNA decay and transcriptional repression of P0.