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1.
J Immunol ; 210(11): 1790-1803, 2023 06 01.
Article in English | MEDLINE | ID: mdl-37074208

ABSTRACT

IL-18 is a pleiotropic immunoregulatory cytokine of the IL-1 family. IL-18 has been identified as a potent IFN-γ inducer in synergy with IL-12 and IL-15 and thus as a powerful Th1 cell-polarizing cytokine. IL-18 activity is regulated by its naturally occurring soluble inhibitor IL-18 binding protein (IL-18BP), the production of which is stimulated by IFN-γ in a negative feedback loop. Circulating levels of IL-18BP are elevated, and unbound bioactive free IL-18 is thus not detectable in the circulation in physiologic conditions. However, emerging evidence indicates that the IL-18/IL-18BP balance could be dysregulated in macrophage activation syndrome (MAS), as mirrored by the presence of free IL-18 in the circulation of patients with MAS. Herein, we sought to identify IL-18BP-producing cells in a murine CpG-induced MAS model using IL-18BP knock-in tdTomato reporter mice. Endothelial cells, tissue-resident macrophages, and neutrophils appeared as major cellular sources of IL-18BP. We also identified extramedullary and medullary early erythroid progenitors as IL-18BP-producing cells in an IFN-γ-dependent manner. This finding suggests a novel regulation of IL-18 activity by erythroid precursors, which are likely involved in the prevention of the negative effects of IL-18 on erythropoiesis. Indeed, coherent in vivo and in vitro results indicate that IL-18 indirectly impairs erythropoiesis while favoring myelopoiesis and thus contributes to anemia associated with MAS and potentially with other IL-18-driven inflammatory diseases. In conclusion, IL-18BP production by endothelial cells, neutrophils, macrophages, and erythroid precursors attenuates the anemia associated with murine CpG-induced MAS.


Subject(s)
Anemia , Macrophage Activation Syndrome , Animals , Mice , Carrier Proteins , Cytokines/metabolism , Endothelial Cells/metabolism , Interleukin-18/metabolism
2.
J Clin Med ; 11(2)2022 Jan 15.
Article in English | MEDLINE | ID: mdl-35054124

ABSTRACT

Interleukin 18 (IL-18) is a pro-inflammatory cytokine of the IL-1 family, whose activity is tightly controlled at the level of production, as well as signalization. Notably, it is buffered by its natural inhibitor, IL-18 binding protein (IL-18BP), which is massively present in circulation in normal and in most pathological conditions, thus preventing harmful pro-inflammatory systemic effects of IL-18. IL-18 has long been considered to be involved in the pathophysiology of various inflammatory diseases. However, a first clinical trial using recombinant IL-18BP for the treatment of rheumatoid arthritis and psoriasis gave disappointing results. Direct measurements of unbound, bioactive, free form of circulating IL-18 demonstrated that IL-18 was more specifically involved in adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) but also in their most severe complication, macrophage activation syndrome (MAS). More importantly, administration of recombinant IL-18BP to patients with AOSD, and sJIA with MAS, showed promising results. This review summarizes available data regarding IL-18 and IL-18BP in AOSD and sJIA in mouse models and humans and shows the importance of IL-18/IL-18BP imbalance in these conditions, leading to the conclusion that IL-18, particularly free IL-18, may be a useful biomarker in these diseases and an interesting therapeutic target.

3.
Cytokine ; 150: 155781, 2022 02.
Article in English | MEDLINE | ID: mdl-34923222

ABSTRACT

Interleukin (IL)-18 is a member of the IL-1 family of cytokines with pleiotropic and potent pro-inflammatory activities that are tightly controlled at the level of production and in the extracellular space. Indeed, IL-18 is translated as a leaderless biologically inert pro-peptide that is cleaved by caspase-1 in its N-terminus domain to become active. Mature Il-18 is then released out of the cells via a phenomenon of inflammatory cell death termed pyroptosis. The biological activity of IL-18 is also regulated by a naturally-occurring soluble inhibitor, IL-18 binding protein (IL-18BP) that binds IL-18 and forms high affinity complexes, thus preventing IL-18 to signal through its cell surface receptors. IL-18BP is present in high amount in the circulation, thus unbound free Il-18 is virtually absent in normal and most pathological conditions. Recent findings showed that IL-18 is present in remarkably high concentrations in some autoinflammatory diseases, including adult-onset Still's disease, systemic juvenile idiopathic arthritis and in various conditions associated with hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Furthermore, elevated levels of free IL-18 are present in correlation with clinical and biological signs of disease activity. Most importantly, some patients with these diseases responded remarkably well to the administration of recombinant human IL-18BP, further indicating the pathogenic role of Il-18 and providing a strong rational for the use of IL-18 inhibitors in some of these difficult to treat auto-inflammatory diseases.


Subject(s)
Macrophage Activation Syndrome , Still's Disease, Adult-Onset , Adult , Humans , Intercellular Signaling Peptides and Proteins , Interleukin-18/metabolism
4.
J Immunol ; 205(4): 1167-1175, 2020 08 15.
Article in English | MEDLINE | ID: mdl-32651219

ABSTRACT

IL-18 binding protein (IL-18BP) acts as a naturally occurring IL-18 decoy receptor. If the balance between IL-18 and IL-18BP is dysregulated, abnormal levels of free bioactive IL-18 are detected, such as in the sera of Il-18bp knockout (KO) mice with CpG-induced macrophage activation syndrome. To determine the cellular sources of Il-18bp in vivo, we selectively depleted Il-18bp expression in either radiosensitive or radioresistant cells using bone marrow transfer between wild-type (WT) and Il-18bp KO mice. Following repeated CpG injections, Il-18bp KO (donor)→ Il-18bp KO (recipient) chimeric mice exhibited more severe disease, with an enhanced Ifn-γ signature and circulating free Il-18 levels, in comparison with WT→WT chimeras. Interestingly, the phenotype of KO→WT and WT→KO mice did not differ from that of WT→WT mice. Consistent with this finding, serum Il-18bp levels were similar in these three groups of mice. The contribution of radioresistant and radiosensitive cells to Il-18bp production varied markedly according to the organ examined, with a major contribution of radiosensitive cells in the spleen as opposed to a major contribution of radioresistant cells in the lung. Finally, Ifn-γ blockade abrogated the CpG-induced but not the constitutive Il-18bp production. Our results demonstrate that circulating Il-18bp is induced in response to Ifn-γ during CpG-induced macrophage activation syndrome and is present at high levels in the circulation to prevent the deleterious systemic effects of Il-18.


Subject(s)
Carrier Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Interleukin-18/metabolism , Macrophage Activation Syndrome/metabolism , Animals , Female , Interferon-gamma/metabolism , Lung/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Spleen/metabolism
5.
Cytokine Growth Factor Rev ; 39: 26-35, 2018 02.
Article in English | MEDLINE | ID: mdl-29366546

ABSTRACT

IL-38 is the most recently discovered cytokine of the IL-1 family and is considered a potential inhibitor of the IL-1 and Toll-like receptor families. IL-38 exerts anti-inflammatory properties, especially on macrophages, by inhibiting secretion of pro-inflammatory cytokines, leading to reduced T-lymphocyte TH17 maturation. IL-38 has been studied most extensively in the context of chronic inflammatory diseases, particularly arthritis, where it is considered an attractive new drug candidate. IL-38 research has entered a new phase, with the realization that IL-38 is important in the pathophysiology of TH17 dependent-diseases (psoriasis, psoriatic arthritis and ankylosing spondylitis). In this review, we provide a critical evaluation of several controversial issues concerning IL-38 function and regulation. There is effectively contrasting data regarding IL-38: it is produced in conditions such as apoptosis, necrosis or inflammation, but data is lacking regarding IL-38 processing and biological function. Furthermore, the receptor for IL-38 has yet to be identified, although three candidate receptors - IL-1R1, IL-36R and IL-1RAPL1-have been proposed. Future studies will hopefully uncover new aspects of this enigmatic cytokine.


Subject(s)
Inflammation/immunology , Interleukins/immunology , Animals , Arthritis, Psoriatic/immunology , Arthritis, Psoriatic/physiopathology , Cell Differentiation/immunology , Humans , Interleukin-1/antagonists & inhibitors , Interleukin-1/immunology , Interleukins/genetics , Mice , Psoriasis/immunology , Psoriasis/physiopathology , Receptors, Cytokine/immunology , Receptors, Interleukin/antagonists & inhibitors , Receptors, Interleukin-1/antagonists & inhibitors , Spondylitis, Ankylosing/immunology , Spondylitis, Ankylosing/physiopathology , Th17 Cells/cytology , Th17 Cells/immunology , Toll-Like Receptors/antagonists & inhibitors , Toll-Like Receptors/immunology
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