Interleukin-1 (IL-1) is also a mediator of the acute inflammatory response and has many similar actions as TNF. The major cellular source of IL-1, like that of TNF, is activated mononuclear phagocytes. Unlike TNF, IL-1 is also produced by many cell types other than macrophages, such as neutrophils, epithelial cells (e.g., kerati-nocytes), and endothelial cells. There are two forms of IL-1, called IL-1 a and IL-1P, that are less than 30% homologous to each other, but they bind to the same cell surface receptors and have the same biologic activities. The main biologically active secreted form is IL-1 P.
IL-1 production usually requires two distinct signals, one that activates new gene transcription and production of a 33-kD precursor pro-IL-1P polypeptide, and a second signal that activates the inflammasome to proteolytically cleave the precursor to generate the 17-kD mature IL-1P protein (see Fig. 4-4). As discussed earlier in the chapter, IL-1P gene transcription is induced by TLR and NOD signaling pathways that activate NF-kB, whereas pro-IL-1 P cleavage is mediated by the NLRP3 inflammasome. IL-1 is secreted by a nonclassical pathway because, unlike most secreted proteins, neither IL-1 a nor IL-1P has hydrophobic signal sequences to target the nascent poly-peptide to the endoplasmic reticulum membrane. One possibility is that mature IL-1 is released mainly when infected cells or activated macrophages die. Some pathogenic bacteria induce both inflammasome-mediated processing of IL-1P and IL-18 in macrophages and caspase-1-dependent cell death, which leads to the release of the inflammatory cytokines. TNF can also stimulate phagocytes and other cell types to produce IL-1. This is an example of a cascade of cytokines that have similar biologic activities.
IL-1 mediates its biologic effects through a membrane receptor called the type I IL-1 receptor, which is expressed on many cell types, including endothelial cells, epithelial cells, and leukocytes. This receptor is an integral membrane protein that contains an extracellular ligand-binding Ig domain and a Toll/IL-1 receptor (TIR) signaling domain in the cytoplasmic region, described earlier in reference to TLRs. The signaling events that occur when IL-1 binds to the type I IL-1 receptor are similar to those triggered by TLRs and result in the activation of NF-kB and AP-1 transcription factors (see Chapter 7). The type II IL-1 receptor appears incapable of activating downstream signals.
IL-6 is another important cytokine in acute inflammatory responses that has both local and systemic effects, including the induction of liver synthesis of a variety of other inflammatory mediators, the stimulation of neutrophil production in the bone marrow, and the differentiation of IL-17-producing helper T cells. IL-6 is synthesized by mononuclear phagocytes, vascular endothelial cells, fibroblasts, and other cells in response to PAMPs and in response to IL-1 and TNF. IL-6 is a homodimer of type I cytokine family polypeptides. The receptor for IL-6 consists of a cytokine-binding polypeptide chain and a signal-transducing subunit (called gp130) that is also the signaling component of receptors for other cytokines. The IL-6 receptor engages a signaling pathway that activates the transcription factor STAT3.
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