Porphyromonas gingivalis fimbriae induce high levels of nuclear factor-kappaB (NF-kappaB)-dependent cytokine release upon primary but not secondary stimulation of monocytic cells (FimA tolerance). In this study, fimbriae induced Toll-like receptor-mediated activation of both p50 and p65 subunits of NF-kappaB upon primary cellular activation. However, activation of the transactivating p65 subunit (but not of the transcriptionally inactive p50 subunit) was significantly inhibited in fimbria-restimulated cells. Moreover, expression of a NF-kappaB-dependent reporter gene was inhibited upon secondary stimulation with fimbriae. NF-kappaB p65 downregulation may thus contribute to induction of FimA tolerance.