PRRs. The PRRs that are able to induce gene expression, which we refer to as signaling PRRs, were unknown until recently, and the first clues as to their nature had been suggested by the homology between mammalian interleukin-1 (IL-1) receptor (IL-1R) and Drosophila Toll receptor signaling pathways. Both receptors activate the NF-κB transcription factor and share a homologous cytoplasmic domain (Toll/IL-1R or TIR domain). Our search for novel proteins containing a TIR domain resulted in identification of a human homolog of the Drosophila Toll protein (Medzhitov et al. 1997). We knew by then that dToll was an essential part of the Drosophila innate immune response to fungal infection, involving the induced production of the antifungal peptide drosomycin (Lemaitre et al. 1996). In the first experiments we performed with a dominant active form of TLR4, we replaced the ectodomain, including much of the juxtamembrane region that contains four half-cysteine residues, with the ectodomain of mouse CD4. This removed three of the four half-cysteine residues and made the gene dominantly active, much as mutating any one of the four half-cysteine residues renders dToll dominantly active, as in the mutant Toll 10B (Belvin and Anderson 1996). When we transfected the human macrophage cell line THP-1 with this construct, we observed that several genes were induced, including the costimulatory molecules B7. 1 and B7. 2, the proinflammatory cytokines IL-1β, IL-6, and IL-12 p40, and the chemokine IL-8 which is a neutrophil attractant. We also observed that the dominant active TLR4 activated the transcription factor NF-κB, giving us a strong clue as to the nature of its signaling pathway (Medzhitov et al. 1997).