Toll-Like Receptor Pathway
The innate immune response responds in a general manner to factors present in invading pathogens. Bacterial factors such as lipopolysaccharides (LPS, endotoxin), bacterial lipoproteins, peptidoglycans and also CpG nucleic acids activate innate immunity as well as stimulating the antigen-specific immune response and triggering the inflammatory response. Members of the toll-like receptor (TLR) gene family convey signals stimulated by these factors, activating signal transduction pathways that result in transcriptional regulation and stimulate immune function. TLR2 is activated by bacterial lipoproteins, TLR4 is activated by LPS, and TLR9 is activated by CpG DNA; peptidoglycan recognition protein (PGRP) is activated by peptidoglycan (PGN). The downstream signaling pathways used by these receptors are similar to that used by the IL-1 receptor, activating the IL-1 receptor associated kinase (IRAK) through the MyD88 adaptor protein, and signaling through TRAF-6 and protein kinase cascades to activate NF-kB and Jun. NF-kB and c-Jun activate transcription of genes such as the proinflammatory cytokines IL-1 and IL-12. Several recent reports have suggested that the functional outcomes of signaling via TLR2, TLR4 and PGRP are not equivalent. For example, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. The intracelular receptor for PGN, PGRP is conserved from insects to mammals. In insects, PGRP activates prophenoloxidase cascade, a part of the insect antimicrobial defense system. Because mammals do not have the prophenoloxidase cascade, its function in mammals is unknown. However, it was suggested that an identical protein Tag7 was a tumor necrosis factor-like (TNF-like) cytokine. PGRP/Tag7 possesses cytotoxicity and triggers intranucleosomal DNA fragmentation in target cells in the same way as many known members of the TNF family. Fragmentation of DNA is one of the characteristics of apoptosis. The possibility that in another system, PGRP/Tag7 would induce NF-kB activation, as observed for TRAIL (TNF-related apoptosis-inducing ligand) receptors canot be ruled out.
Contributor: Glenn Croston, PhD.
REFERENCES: Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000 Aug 17;406(6797):782-7. Kimbrell DA, Beutler B., The evolution and genetics of innate immunity. Nat Rev Genet 2001 Apr;2(4):256-67 Means TK, Golenbock DT, Fenton MJ. Structure and function of Toll-like receptor proteins. Life Sci 2000 Dec 8;68(3):241-58 Yonca Blut, Emmanuelle Faure, et al Cooperation of Toll-Like Receptor 2 and 6 for Cellular Activation by Soluble Tuberculosis Factor and Borrelia burgdorferi Outer Surface Protein A Lipoprotein: Role of Toll-Interacting Protein and IL-1 Receptor Signaling Molecules in Toll-like Receptor 2 Signaling. The Journal of Immunology, 2001, 167: 987-994
