Toll-like receptor signaling and regulation of cytokine gene expression in the immune system.
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 stuctures 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 NFkappaB. 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 alpha/beta) in dendritic cells conferring an antiviral state upon host cells. Moreover, TLR signals stimulate not only pro-inflammatory cytokines such as IFNs, IL-1, TNFalpha, 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.
Ozato
Keiko
K
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA. ozatok@nih.gov
Tsujimura
Hideki
H
Tamura
Tomohiko
T
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism; D029721:Drosophila Proteins / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007113:Immunity, Innate; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D008322:Mammals / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018448:Models, Immunological; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D018417:Th1 Cells / Q000378:metabolism; D051193:Toll-Like Receptors; D014158:Transcription, Genetic
D016207:Cytokines; D029721:Drosophila Proteins; D007378:Interleukins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors