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Annual Review of Immunology 2015Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate... (Review)
Review
Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.
Topics: Animals; Disease Susceptibility; Gene Expression Regulation; Humans; Interleukins; Lymphocytes; Organ Specificity; Signal Transduction; Interleukin-22
PubMed: 25706098
DOI: 10.1146/annurev-immunol-032414-112123 -
Nature Immunology Jul 2012The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with... (Review)
Review
The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with a unique set of connections and functional interactions not shared by other cytokine families. Despite sharing many structural features and molecular partners, cytokines of the IL-12 family mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes that characterize this cytokine family. We also discuss the therapeutic implications of this complexity.
Topics: Humans; Inflammation; Inflammation Mediators; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Protein Multimerization; Signal Transduction; T-Lymphocytes
PubMed: 22814351
DOI: 10.1038/ni.2366 -
Immunity Apr 2019Cytokines are among the most important effector and messenger molecules in the immune system. They profoundly participate in immune responses during infection and... (Review)
Review
Cytokines are among the most important effector and messenger molecules in the immune system. They profoundly participate in immune responses during infection and inflammation, protecting against or contributing to diseases such as allergy, autoimmunity, and cancer. Manipulating cytokine pathways, therefore, is one of the most effective strategies to treat various diseases. IL-10 family cytokines exert essential functions to maintain tissue homeostasis during infection and inflammation through restriction of excessive inflammatory responses, upregulation of innate immunity, and promotion of tissue repairing mechanisms. Their important functions in diseases are supported by data from many preclinical models, human genetic studies, and clinical interventions. Despite significant efforts, however, there is still no clinically approved therapy through manipulating IL-10 family cytokines. Here, we summarize the recent progress in understanding the biology of this family of cytokines, suggesting more specific strategies to maneuver these cytokines for the effective treatment of inflammatory diseases and cancers.
Topics: Animals; Autoimmune Diseases; Cytokines; Gene Expression Regulation; Humans; Immunity, Innate; Infections; Inflammation; Interleukin-10; Interleukins; Lymphocyte Subsets; Mice; Multigene Family; Myeloid Cells; Neoplasms; Signal Transduction; Transcription Factors; Interleukin-22
PubMed: 30995504
DOI: 10.1016/j.immuni.2019.03.020 -
Theranostics 2021Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the... (Review)
Review
Macrophages are specialized cells that control tissue homeostasis. They include non-resident and tissue-resident macrophage populations which are characterized by the expression of particular cell surface markers and the secretion of molecules with a wide range of biological functions. The differentiation and polarization of macrophages relies on specific growth factors and their receptors. Macrophage-colony stimulating factor (CSF-1) and interleukine-34 (IL-34), also known as "twin" cytokines, are part of this regluatory landscape. CSF-1 and IL-34 share a common receptor, the macrophage-colony stimulating factor receptor (CSF-1R), which is activated in a similar way by both factors and turns on identical signaling pathways. However, there is some discrete differential activation leading to specific activities. In this review, we disscuss recent progress in understanding of the role of the twin cytokines in macrophage differentiation, from their interaction with CSF-1R and the activation of signaling pathways, to their implication in macrophage polarization of non-resident and tissue-resident macrophages. A special focus on IL-34, its involvement in pathophsyiological contexts, and its potential as a theranostic target for macrophage therapy will be proposed.
Topics: Animals; Homeostasis; Humans; Interleukins; Macrophage Activation; Macrophage Colony-Stimulating Factor; Macrophages; Signal Transduction
PubMed: 33408768
DOI: 10.7150/thno.50683 -
American Journal of Clinical Dermatology Jan 2022Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or... (Review)
Review
Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or without systemic inflammation. GPP flares can be life-threatening if untreated due to potential severe complications such as cardiovascular failure and serious infections. Currently, there are no GPP-specific therapies approved in the USA or Europe. Retinoids, cyclosporine, and methotrexate are the most commonly used non-biologic therapies for GPP. The evidence that supports the currently available treatment options is mainly based on case reports and small, open-label, single-arm studies. However, recent advances in our understanding of the pathogenic mechanisms of GPP and the identification of gene mutations linked to the disease have paved the way for the development of specific targeted therapies that selectively suppress the autoinflammatory and autoimmune mechanisms induced during GPP flares. Several biologic agents that target key cytokines involved in the activation of inflammatory pathways, such as tumor necrosis factor-α blockers and interleukin (IL)-17, IL-23, and IL-12 inhibitors, have emerged as potential treatments for GPP, with several being approved in Japan. The evidence supporting the efficacy of these agents is mainly derived from small, uncontrolled trials. A notable recent advance is the discovery of IL36RN mutations and the central role of IL-36 receptor ligands in the pathogenesis of GPP, which has defined key therapeutic targets for the disease. Biologic agents that target the IL-36 pathway have demonstrated promising efficacy in patients with GPP, marking the beginning of a new era of targeted therapy for GPP.
Topics: Biological Products; Humans; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Psoriasis; Skin Diseases, Vesiculobullous
PubMed: 35061230
DOI: 10.1007/s40257-021-00658-9 -
Cytokine Aug 2022The IL-36 family of cytokines includes three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ) and a receptor antagonist (IL-36Ra), which bind and signal through... (Review)
Review
The IL-36 family of cytokines includes three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ) and a receptor antagonist (IL-36Ra), which bind and signal through a heterodimeric receptor composed of IL-36R and the IL-1R accessory protein (IL-1RAcP). Individuals with inactivating mutations in the gene encoding IL-36Ra develop generalized pustular psoriasis, a severe form of psoriasis, a finding which clearly links dysregulated IL-36 pathway activation to inflammatory skin conditions. The purpose of this review is to highlight the cellular source of IL-36 cytokines, the effects of IL-36 signaling across cell types, and the association of IL-36 to a spectrum of inflammatory skin diseases including various forms of psoriasis as well as hidradenitis suppurativa, atopic dermatitis, and allergic contact dermatitis.
Topics: Cytokines; Hidradenitis Suppurativa; Humans; Interleukin-1; Interleukins; Psoriasis; Skin
PubMed: 35679693
DOI: 10.1016/j.cyto.2022.155897 -
Blood Jun 2023The bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML)....
The bone marrow microenvironment supports leukocyte mobilization and differentiation and controls the development of leukemias, including acute myeloid leukemia (AML). Here, we found that the development of AML xenotransplants was suppressed in mice with osteoclasts tuberous sclerosis 1 (Tsc1) deletion. Tsc1-deficient osteoclasts released a high level of interleukin-34 (IL-34), which efficiently induced AML cell differentiation and prevented AML progression in various preclinical models. Conversely, AML development was accelerated in mice deficient in IL-34. Interestingly, IL-34 inhibited AML independent of its known receptors but bound directly to triggering receptor expressed on myeloid cells 2 (TREM2), a key hub of immune signals. TREM2-deficient AML cells and normal myeloid cells were resistant to IL-34 treatment. Mechanistically, IL-34-TREM2 binding rapidly phosphorylated Ras protein activator like 3 and inactivated extracellular signal-regulated protein kinase 1/2 signaling to prevent AML cell proliferation and stimulate differentiation. Furthermore, TREM2 was downregulated in patients with AML and associated with a poor prognosis. This study identified TREM2 as a novel receptor for IL-34, indicating a promising strategy for overcoming AML differentiation blockade in patients with AML.
Topics: Animals; Mice; Bone Marrow; Carrier Proteins; Interleukins; Leukemia, Myeloid, Acute; Signal Transduction; Tumor Microenvironment
PubMed: 37001042
DOI: 10.1182/blood.2022018619 -
Frontiers in Immunology 2022Inflammation proteins including interleukins (ILs) have been reported to be related to obstructive sleep apnea (OSA). The aims of this study were to estimate the levels... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Inflammation proteins including interleukins (ILs) have been reported to be related to obstructive sleep apnea (OSA). The aims of this study were to estimate the levels for several key interleukins in OSA and the causal effects between them.
METHOD
Weighted mean difference (WMD) was used to compare the expression differences of interleukins between OSA and control, and the changed levels during OSA treatments in the meta-analysis section. A two-sample Mendelian randomization (MR) was used to estimate the causal directions and effect sizes between OSA risks and interleukins. The inverse-variance weighting (IVW) was used as the primary method followed by several other MR methods including MR Egger, Weighted median, and MR-Robust Adjusted Profile Score as sensitivity analysis.
RESULTS
Nine different interleukins-IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12, IL-17, IL-18, and IL-23-were elevated in OSA compared with control to varying degrees, ranging from 0.82 to 100.14 pg/ml, and one interleukin, IL-10, was decreased by 0.77 pg/ml. Increased IL-1β, IL-6, and IL-8 rather than IL-10 can be reduced in OSA by effective treatments. Further, the MR analysis of the IVW method showed that there was no significant evidence to support the causal relationships between OSA and the nine interleukins-IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, and IL-18. Among them, the causal effect of OSA on IL-5 was almost significant [estimate: 0.267 (-0.030, 0.564), 0.078]. These results were consistent in the sensitivity analysis.
CONCLUSIONS
Although IL-1β, IL-2, IL-4, IL-6, IL-8, IL-12, IL-17, IL-18, and IL-23 were increasing and IL-10 was reducing in OSA, no significant causal relationships were observed between them by MR analysis. Further research is needed to test the causality of OSA risk on elevated IL-5 level.
Topics: Humans; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-18; Interleukin-2; Interleukin-23; Interleukin-4; Interleukin-5; Interleukin-6; Interleukin-8; Sleep Apnea, Obstructive
PubMed: 35967324
DOI: 10.3389/fimmu.2022.888644 -
Nature Medicine Jun 2014Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote...
Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.
Topics: Adoptive Transfer; Animals; Autoimmune Diseases; B-Lymphocytes, Regulatory; Blotting, Western; Chromatin Immunoprecipitation; DNA Primers; Genetic Engineering; Immunoprecipitation; Interleukin-10; Interleukin-12 Receptor beta 2 Subunit; Interleukins; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Uveitis
PubMed: 24743305
DOI: 10.1038/nm.3554 -
Medicine Nov 2023Acute pancreatitis (AP) is one of the most common gastrointestinal diseases, and it is divided into 3 types according to its severity:mild acute pancreatitis, moderately... (Review)
Review
Acute pancreatitis (AP) is one of the most common gastrointestinal diseases, and it is divided into 3 types according to its severity:mild acute pancreatitis, moderately severe acute pancreatitis, and severe acute pancreatitis. The mortality in severe acute pancreatitis is approximately 15% to 30% due to multiorgan dysfunction and the lack of specific treatment. Interleukin-22 (IL-22) is a member of the Interleukin-10 family, and it can activate several downstream signaling pathways by binding to its receptor complex, thus it is involved in cell differentiation, proliferation, and apoptosis. Some studies have reported the elevated level of IL-22 in patients with AP, which suggests IL-22 may be involved in the pathogenesis of AP. And many studies have shown that IL-22 had a protective effect against AP. This article reviews the characteristics and mechanism of IL-22 and its role in AP to provide insight into the treatment of AP.
Topics: Humans; Pancreatitis; Acute Disease; Interleukin-6; Interleukins; Severity of Illness Index; Interleukin-22
PubMed: 37933011
DOI: 10.1097/MD.0000000000035695