Hayashi et al. characterized the transmembrane Toll-like receptor (TLR) 5 protein and identified a physiologically relevant ligand capable of activating TLR5 signaling. Overexpression of chimeric proteins consisting of the intracellular domain of TLR5 fused to the extracellular domain of CD4 (to promote dimerization) resulted in transcription from an NF-κB-dependent gene reporter and led to increased production of tumor necrosis factor α (TNF-α), suggesting that dimerization of the TLR5 cytoplasmic domains is sufficient to activate TLR5-dependent signaling. Flagellin protein from Listeria monocytogenes strongly stimulated TLR5-mediated NF-κB activation. Heterologous expression of Listeria flagellin in an Escherichia coli strain that does not produce endogenous flagellin also activated TLR5, indicating that TLR5 is specifically activated by flagellin. Further experiments revealed that Salmonella flagellin was also able to activate TLR5 signaling, suggesting that both Gram-positive and Gram-negative flagellin are ligands for TLR5. Thus, the activation of TLR5 may function as an alarm response to general infections by flagella-containing bacteria. For a review of Toll, Toll-like, and interleukin-1 receptors, please see the article by O'Neill . F. Hayashi, K. D. Smith, A. Ozinsky, T. R. Hawn, E. C. Yi, D. R. Goodlett, J. K. Eng, S. Akira, D. M. Underhill, A. Aderem, The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410 , 1099-1103 (2001). [Online Journal] L. A. J. O'Neill, The interleukin-1 receptor/toll-like receptor superfamily: signal transduction during inflammation and host defense. Science's STKE (2001), http://www.stke.org/cgi/content/full/OC_sigtrans;2000/44/re1 [Full Text]