The heat shock response is known to inhibit NF-kappaB activation and NF-kappaB-dependent gene expression. Herein we determined if cells lacking heat shock factor-1 (HSF-1), the major transcription factor regulating heat shock protein gene expression, have an altered ability to modulate NF-kappaB activation. Embryonic fibroblasts from HSF-1-null mutant mice (HSF-1-/- cells) had a drastically reduced ability to express heat shock protein-70 in response to heat shock, compared to embryonic fibroblasts from wild-type mice (HSF+/+ cells). There was no difference, however, in the ability of heat shock to inhibit TNFalpha-mediated NF-kappaB activation, IkappaBalpha degradation, IkappaB kinase activation, and macrophage chemotactic protein-1 expression in the HSF-1-/- cells compared to the HSF-1+/+ cells. These data demonstrate that heat shock inhibits activation of the NF-kappaB/IkappaBalpha pathway and NF-kappaB-dependent gene expression in the absence of an intact heat shock response. (C) 2002 Elsevier Science (USA).