Toll-like receptor–mediated NF-κB activation: a phylogenetically conserved paradigm in innate immunity

Innate immunity is an ancient form of host defense that is shared by almost all multicellular organisms (1, 2). However, it is not a redundant defense mechanism, and recent evidence has shown that innate immunity not only provides a first line of antimicrobial host defense, but also has a profound impact on the establishment of adaptive immune responses (1, 3). Upon infection, microorganisms are first recognized by cells of the host innate immune system, such as phagocytic leukocytes, endothelial and mucosal epithelial cells, and professional antigen-presenting cells. Recognition of pathogens is primarily mediated by a set of germline-encoded molecules on innate immune cells that are referred to as pattern recognition receptors (PRRs) (3). Well characterized PRRs include CD14, β2-integrins (CD11/CD18), C-type lectins, macrophage scavenger receptors, and complement receptors (CR1/CD35, CR2/CD21) (3). These PRRs are expressed as either membrane-bound or soluble proteins that recognize invariant molecular structures called pathogen-associated molecular patterns (PAMPs) that are shared by many pathogens but not expressed by hosts (3). Examples of PAMPs include LPS, bacterial lipoprotein (BLP), peptidoglycan (PGN) lipoteichoic acid (LTA), unmethylated CpG DNA of bacteria, lipoarabinomannan (LAM) of mycobacteria, and mannans of yeast (3). Recognition of PAMPs by PRRs results in the activation of different intracellular signaling cascades that in turn lead to the expression of various effector molecules (3). One group of effector molecules consists of reactive oxygen and nitrogen intermediates and various antimicrobial peptides that have direct microbicidal activity and collectively provide immediate protection for hosts. Another group includes cytokines, chemokines, adhesion molecules, and acute phase proteins that are involved in inflammation and early host defense as well as the development of adaptive immune responses. The third group consists of the costimulatory molecules B7.1 and B7.2, which bind CD28 on T cells and act as the second signal for T-cell activation. Therefore, signaling by the PRRs helps to bridge innate and adaptive immunity and allows the host to cope more efficiently with microbial infection. In keeping with the important role that innate immunity plays in protecting multicellular organisms from infection, components of the innate immune response, including pathogen recognition molecules, signal transduction pathways, and downstream effector molecules, are all evolutionarily conserved and are used by insects, plants, and mammals (2). Recent studies on the recognition of microbial PAMPs have highlighted the critical role of one group of PRRs, the Toll-like receptors (TLRs), in pathogen recognition and host defense. These TLRs are distinguished from other PRRs by their ability to recognize and, more significantly, discriminate between, different classes of pathogens (reviewed in refs. 4, 5). Engagement of TLRs by pathogens leads to the activation of innate immune responses (5), and a major signaling target of the TLRs is activation of the transcription factor NF-κB, a key regulator of immune and inflammatory responses (reviewed in refs. 6–8). Interestingly, TLR-mediated NF-κB activation is also an evolutionarily conserved event that occurs in phylogenetically distinct species ranging from insects to mammals (5, 9, 10). Here, we focus on the role of the conserved TLR/NF-κB signaling pathway in innate immunity, as well as its impact on adaptive immune responses.