Trends in Immunology
ReviewIL-17 and IL-22: siblings, not twins
Section snippets
Interleukin (IL)-17 and IL-22 are related, but distinct tissue-signaling leukocytes
IL-17A, IL-17F and IL-22 are leukocyte-derived cytokines that have a major impact on epithelial cells in various tissues. A mass of data on the biology of both cytokines has been collected by the scientific community throughout the past decade. Increasing evidence suggests that IL-17 and IL-22 are key regulators of homeostasis and epithelial barrier function. Both can be protective against infections, but also turn pathological in several inflammatory diseases such as psoriasis, asthma and
Molecular structure of IL-17 and IL-22
IL-17 (specifically IL-17A) was cloned and described in 1993, and originally named as CTLA8 [6]. It belongs to a family of six identified proteins (IL-17A–F) [7]. Of these, the IL17A and IL17F genes share the closest homology and are located on chromosome 6 of the human genome. Only IL-17A and IL-17F are produced by Th17 cells and activated leukocytes, and therefore, are the focus of this review. IL-22 belongs to the IL-10 family of cytokines and was originally described as IL-10-related T
Cellular sources of IL-17 and IL-22
A broad variety of human T cells and other leukocytes secrete IL-17A, IL-17F and/or IL-22 (Table 1), with distinct populations of leukocytes secreting exclusively one of the glycoproteins. It appears that all IL-17-producing leukocytes express the transcription factor RORC, the human analogue to mouse RORγt, and RORC2 is essential for IL-17 production [12]. However, RORC2 expression is not limited to IL-17 secreting T cells and is also expressed in natural regulatory T cells (Tregs) [13]. By
Target cells and receptors of IL-17 and IL-22
IL-17A and IL-17F both bind to two distinct receptors, IL-17RA and IL-17RC. IL-17RA is widely expressed on epithelial cells, fibroblasts, macrophages, dendritic cells, vascular endothelial cells and peripheral blood T lymphocytes 28, 29, 30, 31, while IL-17RC is expressed exclusively on tissue cells of prostate, cartilage, kidney, liver, heart and muscle 32, 33. IL-17RA and IL-17RC are both important for efficient IL-17A and IL-17F signaling in epithelial cells such as synoviocytes, where
Signaling pathways of IL-17 and IL-22
Binding of IL-17A and IL-17F to their receptors results in activation of the transcription factor nuclear factor (NF)-κB [39] (Figure 1). This activation requires the adaptor protein Act1 [40] and the scaffold protein Traf6 [41]. IL-17A and IL-17F have also been shown to activate mitogen-activated protein (MAP) kinases including Erk (IL-17A and IL-17F) and p38 (IL-17A) [42]. In addition to direct effects on gene expression in target cells, IL-17A and IL-17F also function to stabilize tumor
Induction of IL-17 and IL-22: a crucial role for the microenvironment
Th17 (IL-17) immune responses crucially depend on external as well as internal stimuli derived from the local microenvironment. Among external stimuli are infectious triggers called pathogen-associated molecular patterns. These comprise molecules that are derived from extracellular pathogens such as bacteria [47] and fungi [48] that induce the differentiation of naïve T cells into Th17 cells. Other non-infectious triggers such as bleomycin [49] and uric acid [50] are called danger-associated
Effector functions of IL-17 and IL-22
Effects of IL-17 and IL-22 are organ-specific, as anticipated by the receptor distribution on target cells such as epithelial cells (Figure 2). Accordingly, IL-17+ and IL-22+ leukocytes are strongly enriched in peripheral tissue as compared to the circulation 4, 20 and their function should be considered in the context of target organs.
Concluding remarks
IL-17A, IL-17F and IL-22 are structurally similar leukocyte-derived cytokines that bind to distinct receptors and elicit different intracellular pathways. However, IL-17 and IL-22 both belong to a class of mediators with no (IL-22), or little (IL-17), direct effect on immune cells, but with dominant effects on epithelial cells. IL-17 and/or IL-22 are released by many different leukocytes and specific, often pathogen-related, microenvironmental conditions determine their functional outcome,
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