TOXIC EFFECTS OF TETANUS TOXIN ON GG2EE MACROPHAGES - PREVENTION OF GAMMA-INTERFERON-MEDIATED UP-REGULATION OF LYSOZYME-SPECIFIC MESSENGER-RNA LEVELS

By using a nonneuronal cell system, evidence has previously been provi ded that tetanus toxin (TT) intoxication occurs in macrophages, impair ing their secretory activity as well as their antitumoral activity. In particular, both secreted and total lysozyme (LZM) activities are red uced by TT treatment, provided that GG2EE macrophages have been preexp osed 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 macroph ages preexposed to IFN-gamma exhibited augmented levels of LZM-specifi c mRNA. Such an effect was detected 1 h after removal of IFN-gamma, pe aked at 3 h, and gradually decreased with time in culture. Exposure of IFN-gamma-pretreated GG2EE macrophages to TT resulted in the preventi on of the IFN-gamma-mediated upregulation of LZM mRNA levels. The phen omenon was mediated by the holotoxin (greater-than-or-equal-to 1 mug/m l) and abrogated by preexposure of the macrophages to the C fragment o f TT. Protein kinase C (PKC) and Ca2+-calmodulin-dependent PK were lik ely involved in the IFN-gamma-mediated upregulation of LZM mRNA levels and biological activity, as assessed by PK inhibitors. Furthermore, P K inhibitors mimicked TT in impairing LZM activity of GG2EE macrophage s, thus suggesting that impairment of PKC and/or the Ca2+-calmodulin-d ependent PK pathway(s) may be one of the events involved in TT intoxic ation of macrophages.