C17orf99 | |||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
Aliases | C17orf99 , UNQ464, chromosome 17 open reading frame 99, IL-40, IL40, Interleukin 40 | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | MGI: 1924977; HomoloGene: 90660; GeneCards: C17orf99; OMA:C17orf99 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
|
Interleukin 40 (IL-40), also known with other name C17orf99, is a protein belonging to a group of cytokines called interleukins. It is encoded by a gene that does not belong to any cytokine superfamily. [5] This cytokine is produced primarily by human expression tissues such as bone marrow and fetal liver, and its expression can be also induced in peripheral B cells after activation. [6] IL-40 is involved in immunoglobulin A (IgA) production, and plays an important role in humoral immune responses and B cell homeostasis and development. [7] [8]
In October 2017, an article was published [9] concerning a previously uncharacterized gene C17orf99 (chromosome 17 open reading frame 99) which is localized on chromosome 17 (17q25.3). [10] This gene encodes a polypeptide chain with 265 amino acids long sequence (including a 20-aa signal peptide), which further determines the mature small secreted protein with predicted molecular weight of approximately 27 kDa.
Due to its unique sequence, IL-40 is not structurally related to any other cytokine family, suggesting that it has a distinct evolutionary history. Besides IL-40, there are few cytokines that also do not belong to any cytokine superfamily, namely: IL-32 and IL-34. [7]
Since this protein is primarily secreted after B cell activation, it was assumed that the gene product C17orf99 would affect the immune system, however, the precise effects require further investigation. Testing was conducted on mice with targeted chromosomal deletion. The novel cytokine that resulted from the study was designated IL-40 and is the most recent in a line of cytokines found.
Only mammalian genomes contain C17orf99, which is expressed by B cells that have been activated, however the expression profile of IL-40 is similar in two species (mouse and human) and is 72% conserved at the amino acid level between them. [9]
IL-40 has been found is crucial for humoral immune reactions, synthesis of IgA [11] and might be helpful for the growth of B cells, B cell maturation in the BM and in the periphery and their homeostasis. Importantly, human activated B cells and some B cell lymphomas express IL-40 as well. The major producing cells are B cells, bone marrow stroma cells.
IL-40 is associated with lactation and affects initiation of IgA production in the mammary gland. Through the interaction of mucosal immunity and microbiota, the composition of the gut microbiome in mice is also correlated with expression of cytokine IL-40.
Cytokines like IL-4 and TGF-1 can increase the amount of IL-40.
Latter findings imply that it might be related to pathophysiological and inflammatory aspects of diseases.
IL-40 cytokine may play a regulatory role in the pathogenesis of inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, which is a common chronic inflammatory autoimmune rheumatic disorder, diabetes mellitus, [12] several cell lines of human diffuse large B cell lymphoma and also can play some role in autoimmune hepatitis as discriminating autoantigens. [6]
In a disorder called ankylosing spondylitis (AS), [13] it has been discovered to be connected with elevated circulating levels of pro-inflammatory cytokines and additionally, it has been revealed that anti-inflammatory cytokines are crucial for AS immunological homeostasis such as interleukin (IL)-1 family, in that it includes both pro-inflammatory (IL-1α, IL-1β, IL-18, IL-33, and IL-36) and anti-inflammatory (IL-37 and IL-38) cytokines. It has been revealed that IL-40 was significantly higher in AS patients than in controls, and it can be used as biomarker with other cytokines in serum of patients. [14] [15] [16]
Given the association of IL-40 with B cells homeostasis [17] and the crucial role of B cells in autoimmunity, [17] it only makes sense to focus on this cytokine during studies of rheumatoid arthritis or autoimmunity in general. Exploring IL-40 as a potential biomarker for earlier diagnosis of these diseases could lead to improvement in therapeutic outcomes. Additionally, there is potential to leverage IL-40 in therapeutic interventions. [18]
The expression of IL-40, an interleukin involved in immune regulation, has been found to be elevated in the synovial fluid of patients with rheumatoid arthritis. [17] RA is characterized by autoimmune reactions primarily targeting the synovial membrane, [19] making the synovial fluid a valuable medium for studying molecules that interact with or originate from this membrane. A comparison of IL-40 expression in synovial tissue between RA and osteoarthritis (OA) patients reveals significantly higher levels in RA patients, particularly within the inflammatory infiltrate. Within the synovial tissue of RA patients, IL-40 is observed to co-localize with various immune cells such as macrophages, B cells, T cells, and neutrophils. [17] Neutrophils, in particular, have been identified as a known source of IL-40 in the context of RA. [17]
In addition to its presence in the synovial fluid, IL-40 levels are elevated in the serum of RA patients compared to those with OA. However, the concentration of IL-40 is notably higher in the local inflammatory sites, specifically the RA synovial fluid, compared to levels of IL-40 in serum. [17] [18]
IL-40 in RA patients is correlated with disease activity and the levels of autoantibodies. [17] Furthermore, during the early stages of RA, IL-40 is elevated in the serum compared to healthy individuals. However, after three months of conventional therapy, IL-40 levels in the early stages of RA can be normalized. [18] Studies have shown that elevated IL-40 levels in RA decrease following B-cell depletion therapy, as demonstrated by the effects of rituximab on serum IL-40 after 16 and 24 weeks of therapy [17]
Serum levels of IL-40 in early RA correlate with the levels of autoantibodies and NETosis markers. These correlations become evident when neutrophils are stimulated to undergo NETosis or when they are exposed to inflammatory factors like IL-1β, IL-8, tumor necrosis factor, or lipopolysaccharide. Following the induction of NETosis or exposure to inflammatory cytokines, neutrophils showed enhanced secretion of IL-40, indicating their potential involvement in the heightened IL-40 levels observed among early RA patients. [17] [18]
For ankylosing spondylitis (AS) IL-40 has a potential relevance as a biomarker. The levels of IL-40 are significantly higher in the serum of AS patients in comparison with healthy controls (HCs). IL-40 might have excellent diagnostic performance, suggesting its potential as a biomarker for AS susceptibility. [20] IL-40 levels were upregulated in serum of AS patients regardless of age, disease duration, disease activity or HLA-B27. [20] This observation is relevant to AS since it is suggested that the gut microbiota plays a role in the development of the condition. [20]
IL-40, an interleukin associated with inflammatory diseases, emerges as a promising candidate in the search for biomarkers linked to type 2 diabetes mellitus (T2DM). In T2DM, a condition characterized by a mild form of inflammation, there is a growing hypothesis suggesting that IL-40 may play a role in its development. Levels of IL-40 in serum of T2DM patients were significantly elevated in comparison to HCs. [12]
What makes these findings particularly compelling is that the observed differences in IL-40 levels remain statistically significant even after accounting for various factors that could potentially influence the results. These factors include age, gender, disease duration and body mass index, diabetic neuropathy, fasting plasma glucose levels, and glycated hemoglobin. [12] Thus, IL-40 not only stands out as an excellent predictor for distinguishing between individuals with T2DM and healthy individuals but also demonstrates its significance as an independent biomarker. [12]
Furthermore, IL-40 levels uncover a negative correlation between IL-40 and both age and age of onset. This relationship suggests that IL-40 may not only serve as a reliable biomarker for distinguishing individuals with T2DM but also provide insights into the progression and onset of the disease. [12] The elevated IL-40 levels found in the serum of T2DM patients present a compelling case for considering IL-40 as a valuable and reliable biomarker in clinical settings, facilitating the identification and differentiation of individuals with T2DM from healthy counterparts. [12]
Recently, an implication of IL-40 in the pathogenesis of primary Sjögren syndrome (pSS) and pSS-associated lymphoma was investigated. Overexpression of IL-40 was demonstrated in the salivary glands of patients with pSS, particularly in lymphocytic infiltrates and ductal epithelial cells, when compared to non-Sjögren's syndrome patients (nSS). IL-40 was also up-regulated in patients with pSS-associated lymphoma in comparison to nSS. [21] The expression of IL-40 was associated with the degree of inflammatory infiltrate in the salivary glands, [21] which suggests a potential role of IL-40 in driving the inflammatory response. The tissue expression of IL-40 correlated with the expression levels of IL-4 and TGF-β. [21]
In comparison to nSS patients, CD19+ B lymphocytes were the major source of IL-40 in the lymphatic-infiltrated glands of pSS patients.
[21] Furthermore, pSS patients had an expanded population of CD19+IL-40+ B cells in peripheral blood mononuclear cells compared to HCs. [21] In addition, IL-40 was elevated in the serum of patients with pSS compared to nSS and significantly correlated with the disease activity score EULAR Sjögren’s Syndrome Disease Activity Index. (citace) Moreover, a positive association was found between IL-40 levels and anti-SSA (Sjögren Syndrome related antigen A) and immunoglobulin (Ig) levels. [21] In in vitro conditions, recombinant IL-40 significantly enhanced the expression of proinflacmmatory cytokines in T cells and IFN-γ production by B cells, both isolated from pSS patients. [21] Moreover, recombinant IL-40 stimulated NETosis in neutrophils from pSS patients. [21]
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts that functions as a cytokine. The pharmaceutical analogs of naturally occurring GM-CSF are called sargramostim and molgramostim.
Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.
Interleukin-1 beta (IL-1β) also known as leukocytic pyrogen, leukocytic endogenous mediator, mononuclear cell factor, lymphocyte activating factor and other names, is a cytokine protein that in humans is encoded by the IL1B gene. There are two genes for interleukin-1 (IL-1): IL-1 alpha and IL-1 beta. IL-1β precursor is cleaved by cytosolic caspase 1 to form mature IL-1β.
Interleukin-22 (IL-22) is protein that in humans is encoded by the IL22 gene.
Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.
Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.
Osteoimmunology is a field that emerged about 40 years ago that studies the interface between the skeletal system and the immune system, comprising the "osteo-immune system". Osteoimmunology also studies the shared components and mechanisms between the two systems in vertebrates, including ligands, receptors, signaling molecules and transcription factors. Over the past decade, osteoimmunology has been investigated clinically for the treatment of bone metastases, rheumatoid arthritis (RA), osteoporosis, osteopetrosis, and periodontitis. Studies in osteoimmunology reveal relationships between molecular communication among blood cells and structural pathologies in the body.
Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.
Chitinase-3-like protein 1 (CHI3L1), also known as YKL-40, is a secreted glycoprotein that is approximately 40kDa in size that in humans is encoded by the CHI3L1 gene. The name YKL-40 is derived from the three N-terminal amino acids present on the secreted form and its molecular mass. YKL-40 is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells, vascular smooth muscle cells, and hepatic stellate cells. The biological function of YKL-40 is unclear. It is not known to have a specific receptor. Its pattern of expression is associated with pathogenic processes related to inflammation, extracellular tissue remodeling, fibrosis and solid carcinomas and asthma.
Interleukin 20 receptors (IL20R) belong to the IL-10 family. IL20R are involved in both pro-inflammatory and anti-inflammatory immune response. There are two types of IL20R: Type I and Type II.
Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.
Secukinumab, sold under the brand name Cosentyx among others, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis.
Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 consists of a heterodimer between IL-12Rβ1 and IL-23R.
Interleukin 36, or IL-36, is a group of cytokines in the IL-1 family with pro-inflammatory effects. The role of IL-36 in inflammatory diseases is under investigation.
Interleukin-38 (IL-38) is a member of the interleukin-1 (IL-1) family and the interleukin-36 (IL-36) subfamily. It is important for the inflammation and host defense. This cytokine is named IL-1F10 in humans and has similar three dimensional structure as IL-1 receptor antagonist (IL-1Ra). The organisation of IL-1F10 gene is conserved with other members of IL-1 family within chromosome 2q13. IL-38 is produced by mammalian cells may bind the IL-1 receptor type I. It is expressed in basal epithelia of skin, in proliferating B cells of the tonsil, in spleen and other tissues. This cytokine is playing important role in regulation of innate and adaptive immunity.
Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.
Roberto Paganelli is an Italian physician, clinical immunologist and academic. He formerly was a Professor of Internal Medicine at the D'Annunzio University of Chieti–Pescara.
Iain Blair McInnes is a Scottish rheumatologist, Vice Principal and Head of the College of Medical, Veterinary and Life Sciences, Muirhead Chair of Medicine and Versus Arthritis Professor of Rheumatology at the University of Glasgow. His research has focused on inflammatory diseases, particularly rheumatoid arthritis and psoriatic arthritis.