IL-10 family of cytokines
Introduction
Cytokines are small proteins that are secreted by cells, mostly after their activation, and then affect cells, that bear the matching transmembrane receptor. In fact, on the target cells, the cytokine binding to the extracellular moiety of the receptor induces, mediated by the receptor intracellular moiety, a coordinated series of events within the cell that lead to, e.g. changed gene expression patterns, altered cytoskeleton organization, or release of secretory vesicles. Cytokines play a decisive role in the communication between cells and are therefore key players in physiological and pathological processes in multi-cellular organisms. In recent years, this fact has been increasingly utilized in the development of new powerful medications to treat chronic inflammatory diseases.
Based on specific similarities, cytokines are categorized. It should be mentioned that there are many different categorization strategies for cytokines based on either their structural or functional properties. For example, it is now accepted that helical cytokines can be divided into two classes by the primary structural features of their receptors. The class 1 cytokines, including IL-2, IL-4, IL-6, and IL-12, utilize receptors of the cytokine receptor family class 1 (CRF1). The extracellular moieties of these receptors contain one or more copies of a domain with a conserved disulfide bridge and a membrane-proximal sequence of tryptophan-serine-X-tryptophan-serine (WSYWS). In contrast, the class 2 cytokines share the members of the CRF2 that lack the intact WSYWS motif. The class 2 cytokines consist of the different types of IFNs, i.e. type I IFNs, IFN-γ, type III IFNs (IL-28α, IL-28β, and IL-29), as well as six IL-10-related cytokines. The latter, i.e. IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26, were further subgrouped in 2001/2002, namely into the IL-10 family of cytokines [1], [2], [3].
All members of the IL-10 family have the following features: clustering of their encoding genes, similar genomic structures, similar primary and secondary protein structures, and utilization of similar receptor complexes.
In fact, these six proteins are encoded by genes that are found in the human genome in two clusters and have very similar exon–intron structures. Interestingly, the cytokines whose genes are found in the same cluster are produced under similar conditions (by similar cells). These co-expressions may be due to: (i) super-ordinate regulatory elements spanning the locus or (ii) similarity of promoters (i.e. as a consequence of gene duplications).
The amino acid (aa) identity between the members of the IL-10 family is approximately 9–40% whereby characteristic aa positions are conserved. Despite the relatively low sequence identity, all family members show a strikingly similar secondary structure [4].
The receptor complexes that the IL-10 family members operate through are composed of two different CRF2 receptor chains, one R1-type chain and one R2-type chain.
Despite their structural relation and their use of similar or partly identical receptors, members of the IL-10 family possess different biological functions.
The following review will focus on the common and most important aspects of the IL-10 cytokine family members. More detailed descriptions of the biology of IL-10, IL-19, IL-20, IL-22, IL-24, and IL-26 are provided in special review articles of this current issue of Cytokine & Growth Factor Reviews [5], [6], [7], [8], [9], [10].
Section snippets
Genes and proteins
The genes encoding human IL-10, IL-19, IL-20, and IL-24 are located on the chromosome 1 (1q32), in a 195 kbp cluster. The human IL26 and IL22 genes are located on the longer arm of chromosome 12, on 12q15, approximately 42 kbp upstream from the IFNG locus, and have the same transcriptional orientation as IFNG gene (minus strand) (Table 1).
All these genes have the same basic structure (Fig. 2). They comprise five (IL10, IL19, IL20, IL22, and IL26) and six (IL24) protein-coding exons. In addition
The cellular sources
The six members of the IL-10 family can be divided into two groups with respect to their cellular sources. IL-10, IL-22, and IL-26 form the first group and are preferentially produced by immune cells. In contrast, IL-19, IL-20, and IL-24 can be secreted both by tissue cells and immune cells (Fig. 1).
The main source of IL-10 in vivo appears to be monocytes, macrophages, and different T-cell subsets [10]. Moreover, dendritic cells, B-cells, NK-cells, mast cells, as well as neutrophilic and
Receptors
The pleiotropic activities of IL-10 family members are mediated by specific cell surface receptor complexes that each consist of an R1 chain and an R2 chain (see below), both being members of the CRF2 (Fig. 1). Similar to their ligands, the genes encoding these CRF2 members are grouped in genomic regions. These transmembrane proteins, whose N-terminus is located extra cellularly, are characterized by their extra cellular components that are composed of approximately 210 aa and contain two
Biological effects and role in diseases
Surprisingly, despite their structural relation and their use of similar or partly identical receptors, members of the IL-10 family mostly possess different biological functions. This can best be viewed when the effects of IL-10 and IL-22 are compared.
IL-10 is known as one of the most important anti-inflammatory and immunosuppressive cytokines that has major affects on monocytic cells [10], [68]. IL-10 influences three important functions of the monocytes/macrophages: the antigen presentation,
Conclusions
The members of IL-10 family of cytokines share many similarities. However, they possess different biological functions. The currently known facts regarding the effects of these six immune mediators give the impression that at least IL-10, IL-20, and IL-22 play an important role in the pathogenesis of some chronic inflammatory diseases.
In diseases with an IL-10 over-production, undesired immunosuppressive effects of IL-10 and the growth of some tumors can be observed. In diseases with a relative
Acknowledgments
I would like to thank Elizabeth Wallace, Annette Buss, Ellen Witte, and Kerstin Wolk for accurately proofreading the manuscript and the assistance.
Robert Sabat (born in 1969 in Poland) is the director of the Molecular Immunopathology interdisciplinary department at the University Hospital Charité in Berlin, Germany. In 1995, he graduated from the Humboldt University medical school in Berlin, Germany. Subsequently, he completed his medical internship and residency at the Institute for Medical Immunology, University Hospital Charité, Berlin. His medical doctorate thesis focused on interleukin-10. In 1999, he went to the Department of
References (112)
- et al.
The interleukin-10 family of cytokines
Trends Immunol
(2002) The family of IL-10-related cytokines and their receptors: related, but to what extent?
Cytokine Growth Factor Rev
(2002)- et al.
IL-10 and its homologs: important immune mediators and emerging immunotherapeutic targets
Trends Immunol
(2001) Stru ctural analysis of cytokines comprising the IL-10 family
Cytokine Growth Factor Rev
(2010)- et al.
mda-7/IL-24: a unique member of the IL-10 gene family promoting cancer-targeted toxicity
Cytokine Growth Factor Rev
(2010) - et al.
Interleukin-26: an IL-10-related cytokine produced by Th17 cells
Cytokine Growth Factor Rev
(2010) Interleukin-19: multiple roles in immune regulation and disease
Cytokine Growth Factor Rev
(2010)IL-20: biological functions mediated through two types of receptor complexes
Cytokine Growth Factor Rev
(2010)- et al.
Interleukin-22: a cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection
Cytokine Growth Factor Rev
(2010) - et al.
Biology of interleukin-10
Cytokine Growth Factor Rev
(2010)
Structural conservation of interferon gamma among vertebrates
Cytokine Growth Factor Rev
Implications of cytokine gene polymorphisms on the orchestration of the immune response: lessons learned from oral diseases
Cytokine Growth Factor Rev
Cytokine and cytokine receptor gene polymorphisms and their functionality
Cytokine Growth Factor Rev
Crystal structure of interleukin-19 defines a new subfamily of helical cytokines
J Biol Chem
Structure of IL-22 bound to its high-affinity IL-22R1 chain
Structure
Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site
Immunity
Crystal structure of recombinant human interleukin-22
Structure
Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon gamma
Structure
The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains
J Biol Chem
Multiparametric analysis of cytokine-driven human Th17 differentiation reveals a differential regulation of IL-17 and IL-22 production
Blood
IL-22 increases the innate immunity of tissues
Immunity
Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts
Gastroenterology
Expression and suppressive effects of interleukin-19 on vascular smooth muscle cell pathophysiology and development of intimal hyperplasia
Am J Pathol
Detection of IL-20 and its receptors on psoriatic skin
Clin Immunol
The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy
Cytokine
The Class II cytokine receptor (CRF2) family: overview and patterns of receptor-ligand interactions
Cytokine Growth Factor Rev
IFNgamma signaling-does it mean JAK-STAT?
Cytokine Growth Factor Rev
Interferon and cytokine responses to SARS-coronavirus infection
Cytokine Growth Factor Rev
Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells
Cytokine Growth Factor Rev
Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions
J Biol Chem
Interferon-gamma: a historical perspective
Cytokine Growth Factor Rev
Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma-induced genes by suppressing tyrosine phosphorylation of STAT1
Blood
The many faces of the SOCS box
Cytokine Growth Factor Rev
Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10
J Biol Chem
Crosstalk via the NF-kappaB signaling system
Cytokine Growth Factor Rev
Physiological functions of tumor necrosis factor and the consequences of its pathologic overexpression or blockade: mouse models
Cytokine Growth Factor Rev
IkappaB kinase beta (IKKbeta/IKK2/IKBKB)—a key molecule in signaling to the transcription factor NF-kappaB
Cytokine Growth Factor Rev
Three decades of psoriasis research: where has it led us?
Clin Dermatol
Interleukin 20: discovery, receptor identification, and role in epidermal function
Cell
Selective enhancement of multipotential hematopoietic progenitors in vitro and in vivo by IL-20
Blood
The IL-10R1 S138G loss-of-function allele and ulcerative colitis
Genes Immun
Association analysis of IL20RA and IL20RB genes in psoriasis
Genes Immun
Possible relations between the polymorphisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis
Genes Immun
Genome-wide association identifies multiple ulcerative colitis susceptibility loci
Nat Genet
Genetic, epidemiological and biological analysis of interleukin-10 promoter single-nucleotide polymorphisms suggests a definitive role for −819C/T in leprosy susceptibility
Genes Immun
Distal and proximal interleukin (IL)-10 promoter polymorphisms associated with risk of cutaneous melanoma development: a case–control study
Genes Immun
Crystal structure of interleukin 10 reveals an interferon gamma-like fold
Biochemistry
Structure of insect-cell-derived IL-22
Acta Crystallogr D: Biol Crystallogr
Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri
J Virol
Cutting edge: immune cells as sources and targets of the IL-10 family members?
J Immunol
Cited by (0)
Robert Sabat (born in 1969 in Poland) is the director of the Molecular Immunopathology interdisciplinary department at the University Hospital Charité in Berlin, Germany. In 1995, he graduated from the Humboldt University medical school in Berlin, Germany. Subsequently, he completed his medical internship and residency at the Institute for Medical Immunology, University Hospital Charité, Berlin. His medical doctorate thesis focused on interleukin-10. In 1999, he went to the Department of Dermatology at Schering Inc. to work as a research group head for 3 years. During this time, he directed two projects: “Molecular mechanisms of the immunosuppressive effects of interleukin-10” and “New members of the cytokine receptor family class 2”. The Molecular Immunopathology department of the Charité Berlin, which he has been charged with since 2003, links clinical research at the Department of Dermatology with basic science at the Institute for Medical Immunology. His main research interests lie in: the function of novel interleukin-10 related cytokines and the pathogenesis of chronic inflammatory diseases.