The apoptotic signaling pathway activated by Toll-like receptor-2

The innate immune system uses Toll family receptors to signal for the prese nce of microbes and initiate host defense. Bacterial lipoproteins (BLPs), w hich are expressed by all bacteria, are potent activators of Toll-like rece ptor-2 (TLR2). Here we show that the adaptor molecule, myeloid differentiat ion factor 88 (MyD88), mediates both apoptosis and nuclear factor-kappa B ( NF-kappa B) activation by BLP-stimuiated TLR2, Inhibition of the NF-kappa B pathway downstream of MyD88 potentiates apoptosis, indicating that these t wo pathways bifurcate at the level of MyD88, TLR2 signals for apoptosis thr ough MyD88 via a pathway involving Fas-associated death domain protein (FAD D) and caspase 8, Moreover, MyD88 binds FADD and is sufficient to induce ap optosis, These data indicate that TLR2, is a novel 'death receptor' that en gages the apoptotic machinery without a conventional cytoplasmic death doma in. Through TLR2, BLP induces the synthesis of the precursor of the pro-inf lammatory cytokine interleukin-1 beta (TL-1 beta). Interestingly, BLP also activates caspase 1 through TLR2, resulting in proteolysis and secretion of mature IL-1 beta, These results indicate that caspase activation is an inn ate immune response to microbial pathogens, culminating in apoptosis and cy tokine production.