The Interleukin-1 Receptor/Toll-Like Receptor Superfamily: Signal Transduction During Inflammation and Host Defense

The signal transduction pathways activated by the proinflammatory cytokine interleukin-1 (IL-1) have been the focus of much attention because of the important role that IL-1 plays in inflammatory diseases. A number of proteins have been described that participate in the post-receptor activation of the transcription factor nuclear factor κB (NF-κB), and stress-activated protein kinases such as p38 mitogen-activated protein kinase (MAPK). It has also emerged that the type I IL-1 receptor (IL-1RI) is a member of an expanding receptor superfamily. These related receptors all have sequence similarity in their cytosolic regions. The family includes the Drosophila melanogaster protein Toll, the IL-18 receptor (IL-18R), and 10 Toll-like receptors (TLRs), TLR-1 to TLR-10, which bind to microbial products, activating host defense responses. Because of the similarity of IL-1RI to Toll, the conserved sequence in the cytosolic region of these proteins has been termed the Toll-IL-1 receptor (TIR) domain. The same proteins activated during signaling by IL-1RI also participate in signaling by other receptors with TIR domains. The receptor superfamily is evolutionarily conserved; members also occur in plants and insects, where they also function in host defense. The signaling proteins that are activated are also conserved across species. Differences are, however, starting to emerge in signaling pathways activated by different receptors. This receptor superfamily, therefore, represents an ancient signaling system that is a critical determinant of the innate immune and inflammatory responses. The interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily plays a central role in inflammation and the host response to bacterial infection. It includes receptors for the cytokines IL-1 and IL-18, which are secreted during inflammation and during infection in response to microbial products. Products released by a diverse range of microbes act through TLRs, a notable example being lipopolysaccharide (LPS) from gram-negative bacteria, which stimulates TLR-4. Recognition of such microbes by TLRs provokes host defenses against these microbes. Members of the TLR family occur in species from diverse taxa, including mammals, plants, and insects. In insects, receptors such as Toll are also involved in development. The Toll-IL-1 receptor (TIR) domain occurs in the cytosolic region of all superfamily members and triggers the activation of transcription factors, such as nuclear factor κB (NF-κB). It also activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun NH2-terminal kinase (JNK). These signals lead to increased expression of proteins involved in immunity and inflammation, resulting in defenses against infectious agents or to chronic inflammation in autoimmune diseases. NF-κB binding sites occur in the promoters of a large number of immune genes, and the signaling pathway to NF-κB is known in detail. Also being uncovered are differences in signaling between TLRs that lead to the tailoring of innate immune responses to the provoking pathogen. The IL-1R/TLR system is therefore evolutionarily conserved and is a critical determinant of innate immune and inflammatory responses.