Toxic effects of tetanus toxin on GG2EE macrophages: prevention of gamma interferon-mediated upregulation of lysozyme-specific mRNA levels.

By using a nonneuronal cell system, evidence has previously been provided that tetanus toxin (TT) intoxication occurs in macrophages, impairing their secretory activity as well as their antitumoral activity. In particular, both secreted and total lysozyme (LZM) activities are reduced by TT treatment, provided that GG2EE macrophages have been preexposed to gamma interferon (IFN-gamma). In an attempt to provide insight into the molecular mechanisms underlying this phenomenon, we focused our attention on the levels of LZM-specific transcripts. GG2EE macrophages preexposed to IFN-gamma exhibited augmented levels of LZM-specific mRNA. Such an effect was detected 1 h after removal of IFN-gamma, peaked at 3 h, and gradually decreased with time in culture. Exposure of IFN-gamma-pretreated GG2EE macrophages to TT resulted in the prevention of the IFN-gamma-mediated upregulation of LZM mRNA levels. The phenomenon was mediated by the holotoxin (> or = 1 micrograms/ml) and abrogated by preexposure of the macrophages to the C fragment of TT. Protein kinase C (PKC) and Ca(2+)-calmodulin-dependent PK were likely involved in the IFN-gamma-mediated upregulation of LZM mRNA levels and biological activity, as assessed by PK inhibitors. Furthermore, PK inhibitors mimicked TT in impairing LZM activity of GG2EE macrophages, thus suggesting that impairment of PKC and/or the Ca(2+)-calmodulin-dependent PK pathway(s) may be one of the events involved in TT intoxication of macrophages.