Activation of heat shock factor 1 by pyrrolidine dithiocarbamate is mediated by its activities as pro-oxidant and thiol modulator

Pyrrolidine dithiocarbamate (PDTC) is known to inhibit NF-kappaB, which pla ys a critical role(s) as an immediate early mediator of immune and inflamma tory responses. Here we show that PDTC induces heat shock factor 1 (HSF1) a ctivation and heat shock protein expression, while other antioxidants such as butylated hydroxytoluene (BHT), n-propylgallate (PG), ascorbic acid (AA) , and N-acetyl-L-cysteine (NAC) do not. Since PDTC exerts other functions t han antioxidant, e.g., a pro-oxidant, metal chelator, and thiol group modul ator, we examined which of these activities is responsible for the PDTC-ind uced HSF1 activation. PDTC-induced HSF1 activation was not prevented by met al chelators, EDTAs, indicating that the metal chelating effect of PDTC is not linked to the HSF1 activation. PDTC increased intracellular GSSG level. In addition, PDTC-induced activation of HSF1 was significantly inhibited b y NAC and a thiol-reducing agent dithiothreitol (DTT), while it was partial ly prevented by other antioxidants, AA, BHT, and PG. These results suggest that the activation of HSF1 by PDTC may be due to its activities as pro-oxi dant and thiol group modulator rather than anti-oxidant. (C) 2001 Academic Press.