IL-17 and IL-22: siblings, not twins

doi:10.1016/j.it.2010.06.004

Trends in Immunology

Volume 31, Issue 9, September 2010, Pages 354-361

https://doi.org/10.1016/j.it.2010.06.004 Get rights and content

T helper (Th) cell subsets secrete cytokines that regulate other immune cells. Interleukin (IL)-17 and IL-22 belong to a new class of cytokines with predominant effects on epithelial cells. Thus, these cytokines are key molecules in several disease processes. IL-17 and IL-22 are released by leukocytes such as Th and natural killer cell populations. Both IL-17 and IL-22 induce an innate immune response in epithelial cells, but their functional spectra are generally distinct. IL-17 induces an inflammatory tissue response and is involved in the pathogenesis of several autoimmune diseases, whereas IL-22 is protective/regenerative. This review juxtaposes IL-17 and IL-22 and describes overlaps and differences regarding their cellular sources, biochemical structure, signaling cascades in target cells, and function.

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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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

Molecular structure of IL-17 and IL-22

Cellular sources of IL-17 and IL-22

Target cells and receptors of IL-17 and IL-22

Signaling pathways of IL-17 and IL-22

Induction of IL-17 and IL-22: a crucial role for the microenvironment

Effector functions of IL-17 and IL-22

Concluding remarks

Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism

Cancer Res.

Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells

Nat. Immunol.

Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells

Nat. Immunol.

Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways

Br. J. Dermatol.

CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene

J. Immunol.

Interleukin-17 family members and inflammation

Immunity

IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes

Genes Immun.

An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment

J. Immunol.

Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R

J. Biol. Chem.

Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains

Biophys. J.

The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat

Nat. Immunol.

Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

J. Exp. Med.

Expression of IL-17 in human memory CD45RO+ T lymphocytes and its regulation by protein kinase A pathway

Cytokine

Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair?

Nat. Rev. Immunol.

gammadelta T cells: an important source of IL-17

Curr. Opin. Immunol.

IL-17, produced by lymphocytes and neutrophils, is necessary for lipopolysaccharide-induced airway neutrophilia: IL-15 as a possible trigger

J. Immunol.

Phenotypic and functional features of human Th17 cells

J. Exp. Med.

IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha

J. Immunol.

Late developmental plasticity in the T helper 17 lineage

Immunity

Unique phenotype of human tonsillar and in-vitro-induced FOXP3+CD8+ T cells

J. Immunol.

Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine

Cell Host Microbe

Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense

Immunity

Microbial lipopeptides induce the production of IL-17 in Th cells

J. Immunol.

Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses

Immunity

TLR-2 and IL-17A in chitin-induced macrophage activation and acute inflammation

J. Immunol.

The profile of gene expression of human marrow mesenchymal stem cells

Stem Cells

Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection

J. Exp. Med.

Interleukin-17 family and IL-17 receptors

Cytokine Growth Factor Rev.

Soluble and transmembrane isoforms of novel interleukin-17 receptor-like protein by RNA splicing and expression in prostate cancer

J. Biol. Chem.

IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood

J. Immunol.

Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes

J. Immunol.

IL-22 increases the innate immunity of tissues

Immunity

IL-22 produced by human NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion

J. Immunol.

A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist

Proc. Natl. Acad. Sci. U. S. A.

NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells

Review
IL-17 and IL-22: siblings, not twins