The magnitude and duration of innate immune responses are regulated by a variety of feedback inhibition mechanisms that limit potential damage to tissues. Whereas the inflammatory response is critically important for protection against microbes, it has the potential to cause tissue injury and disease. Several mechanisms have evolved to provide a break on inflammation, and these mechanisms come into play at the same time as or shortly after the initiation of inflammation. Furthermore, the stimuli for the initiation of many of these control mechanisms include the same PAMPs and DAMPs that induce inflammation. We will describe a selected group of these regulatory mechanisms.
IL-10 is a cytokine that is produced by and inhibits activation of macrophages and dendritic cells. IL-10 inhibits the production of various inflammatory cyto-kines by activated macrophages and dendritic cells, including IL-1, TNF, and IL-12. Because it is both produced by macrophages and inhibits macrophage functions, IL-10 is an excellent example of a negative feedback regulator. It is not clear whether different stimuli may act on macrophages to induce the production of a regulatory cytokine like IL-10 or effector cytokines like TNF and IL-12, or whether the same stimuli elicit production of all these cytokines but with different kinetics. IL-10 is also produced by some nonlymphoid cell types (e.g., keratinocytes). The Epstein-Barr virus contains a gene homologous to human IL-10, and viral IL-10 has the same activities as the natural cytokine. This raises the intriguing possibility that acquisition of the IL-10 gene during the evolution of the virus has given the virus the ability to inhibit host immunity and thus a survival advantage in the infected host. IL-10 is also produced by regulatory T cells, and we discuss IL-10 in more detail in Chapter 14 in this context.
Mononuclear phagocytes produce a natural antagonist of IL-1 that is structurally homologous to the cytokine and binds to the same receptors but is biologically inactive, so that it functions as a competitive inhibitor of IL-1. It is therefore called IL-1 receptor antagonist (IL-1RA). Synthesis of IL-1RA is induced by many of the same stimuli that induce IL-1 production, and some studies in IL-1RA-deficient mice suggest that this inhibitory cytokine is required to prevent inflammatory diseases of joints and other tissues. Recombinant IL-1RA has been developed as a drug that is effective in the treatment of systemic juvenile rheumatoid arthritis and familial fever syndromes in which IL-1 production is dysregu-lated. Regulation of IL-1-mediated inflammation may also occur by expression of the type II receptor, which binds IL-1 but does not transduce an activating signal. The major function of this receptor may be to act as a "decoy" that competitively inhibits IL-1 binding to the type I signaling receptor.
Secretion of inflammatory cytokines from a variety of cell types appears to be regulated by the products of autophagy genes. Autophagy is a mechanism by which cells degrade their own organelles, such as mitochondria, by sequestering them within membrane-bound vesicles and fusing the vesicles with lysosomes. This process requires the coordinated actions of many different proteins that are encoded by autophagy (Atg) genes. Targeted mutations in different Atg genes result in enhanced secretion of type I interferons, IL-1, and IL-18 by various cell types and the development of inflammatory bowel disease. The mechanisms by which Atg proteins impair cytokine synthesis are not well understood, but evidence exists for their binding to and inhibition of RLRs and regulation of inflammasome formation. A role for Atg proteins in regulating innate immune responses is further supported by the discovery that polymorphisms in a human Atg are associated with inflammatory bowel disease.
There are numerous negative regulatory signaling pathways that block the activating signals generated by pattern recognition receptors and inflammatory cytokines. Suppressors of cytokine signaling (SOCS) proteins are inhibitors of JAK-STAT signaling pathways linked to cytokine receptors. TLR signaling in macrophages and dendritic cells induces the expression of SOCS proteins, which limit responses of these cells to exogenous cytokines such as type I interferons. Proinflammatory responses of cells to TLR signaling are negatively regulated by SHP-1, an intracellular protein phosphatase that negatively regulates numerous tyrosine kinase-dependent signaling pathways in lymphocytes. There are many other examples of kinases and phosphatases that inhibit TLR, NLR, and RLR signaling.
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