Toll-Like Receptor Signaling and Regulation of Cytokine Gene Expression in the Immune System

Abstract

Dendritic cells, macrophages, and granulocytes are derived from hematopoietic stem cells and provide a first line of defense against infectious pathogens. Toll-like receptors (TLRs) expressed on these cells recognize molecular structures present in the pathogens. Upon binding of a pathogen ligand, TLRs trigger a cascade of signaling pathways that is conserved from insect to plants to humans, which ultimately activates NFκB. In mammalian cells, this leads to the induction of cytokine genes and the establishment of innate immunity. For example, TLR signals induce type I interferons (IFN α/β) in dendritic cells conferring an antiviral state upon host cells. Moreover, TLR signals stimulate not only pro-inflammatory cytokines such as IFNs, IL-1, TNFα, and IL-12 but also anti-inflammatory cytokines such as IL-10 and IL-6. IL-12 and IL-10 are cytokines that bridge early innate responses and the ensuing specific immune responses. TLR signals also enhance an antigen presentation capacity in dendritic cells and macrophages. Recent studies with mouse and human cells indicate that TLRs activate multiple signaling cascades that involve chromatin structure alterations as well as activation of many transcription factors (e.g., IRF-3, IRF-8/ICSBP, and PU.1). Together, although the basic backbone is conserved throughout evolution, the TLR signaling system in mammalian species has an added complexity to accommodate a mechanism that links innate and adaptive immunity.