Interleukin 35

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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. [1] IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation. [2]

Contents

Structure

IL-35 and its receptor

IL-35 is a dimeric protein composed of IL-12α and IL-27β chains, which are encoded by two separate genes called IL12A and EBI3 (Epstein-Barr virus-induced gene 3), respectively. [3] [4] IL-35 receptor consists of IL-12Rβ2 (part of the IL-12R) and gp130 (part of IL-27R) chains. Compared to these two related interleukins, IL-35 is also able to signal through only one of the aforementioned chains. This was proven in vivo when absence of either of the receptor chains did not influence effects of IL-35. [5] On regulatory B-cells, IL-35 signals through the IL-12Rβ2 and IL-27Rα subunits. [6]

EBI3 is a homologue to IL-12 p40 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphoblastoid cells by EBV infection [7]

Function

Expression

Secreted by regulatory T-cells (Tregs), regulatory B-cells (Bregs) [8] or even CD8+ regulatory T cells, [9] IL-35 suppresses inflammatory responses of immune cells. [10] IL-35 is not constitutively expressed in tissues, but the gene encoding IL-35 is transcribed by vascular endothelial cells, smooth muscle cells and monocytes after activation with proinflammatory stimuli. [11] IL-35 has selective activities on different T-cell subsets; it induces proliferation of Treg cell populations but reduces activity of Th17 cell populations. [12]

Role in disease

Autoimmune conditions

Studies in mice show the absence of either IL-35 chain from regulatory Tregs reduces the cells' ability to suppress inflammation. This has been observed during cell culture experiments and using an experimental model for inflammatory bowel disease. [2] A group of scientists established a CIA (collagen-induced arthritis) mouse model to show suppressive effects of IL-35. Intraperitoneal injection of IL-35 in the tested subjects lowered expression of several factors linked to this disease (such as VEGF and its receptors, TNF-α). [13] The effect of IL-35 in this case seems to be the inhibition of STAT1 signalling pathway. [14] Another experiment performed on a mouse model of EAE has shown, that mice lacking IL-35-producing B cells are unable to recover from the T-cell mediated demyelination but are resistant to infection by pathogenic intracellular microbe Salmonella typhimurium . [8] [15] [16] In T1D (type 1 diabetes), plasma level of IL-35 is lower than healthy individuals. IL-35 production by Tregs is decreased in mouse models of T1D, and administration of IL-35 prevents the development of experimental T1D and reverses established experimental T1D. [17] In T1D patients with remaining C-peptide, IL-35 production by Tregs and Bregs is much higher than T1D patients with no remaining C-peptide. [18]

Infectious diseases

It has been shown that IL-35 increases replication of HBV virus both in vitro and in transgenic mice by targeting its transcription factor HNF4α. [19]

Tumor

Given its suppressive function, IL-35 is also involved in tumor progression and tumor immune surveillance. [20] Elevated circulating IL-35 levels have been found in several human tumors such as acute myeloid leukemia, [21] pancreatic ductal adenocarcinoma [22] and colorectal cancer. [23]

Moreover, Forkhead box protein 3 (Foxp3) as a transcription factor is an essential molecular marker of regulatory T (Treg) cells. Foxp3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β. [24]

Related Research Articles

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">FOXP3</span> Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interleukin 30</span> Protein-coding gene in the species Homo sapiens

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

Gamma delta T cells are T cells that have a γδ T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, γδ T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells. Their highest abundance is in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

<span class="mw-page-title-main">EBI3</span> Protein-coding gene in the species Homo sapiens

Epstein-Barr virus induced gene 3, also known as interleukin-27 subunit beta or IL-27B, is a protein which in humans is encoded by the EBI3 gene.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">IL2RA</span> Mammalian protein found in Homo sapiens

The Interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and the common gamma chain (IL2RG). As the name indicates, this receptor interacts with Interleukin-2, a pleiotropic cytokine which plays an important role in immune homeostasis.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

<span class="mw-page-title-main">IL1RL1</span> Protein-coding gene in the species Homo sapiens

Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.

<span class="mw-page-title-main">Interleukin 23</span> Heterodimeric cytokine acting as mediator of inflammation

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.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

In cell biology, TH9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.

<span class="mw-page-title-main">Interleukin 17F</span>

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.

References

  1. ↑ Behzadi P, Behzadi E, Ranjbar R (March 2016). "IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways" (PDF). Acta Microbiologica et Immunologica Hungarica. 63 (1): 1–25. doi:10.1556/030.63.2016.1.1. PMID   27020866.
  2. 1 2 Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. (November 2007). "The inhibitory cytokine IL-35 contributes to regulatory T-cell function". Nature. 450 (7169): 566–9. Bibcode:2007Natur.450..566C. doi:10.1038/nature06306. PMID   18033300. S2CID   4425281.
  3. ↑ Li X, Fang P, Yang WY, Wang H, Yang X (October 2019). "IL-35, as a newly proposed homeostasis-associated molecular pattern, plays three major functions including anti-inflammatory initiator, effector, and blocker in cardiovascular diseases". Cytokine. 122: 154076. doi:10.1016/j.cyto.2017.06.003. PMC   5741534 . PMID   28648331.
  4. ↑ Su LC, Liu XY, Huang AF, Xu WD (July 2018). "Emerging role of IL-35 in inflammatory autoimmune diseases". Autoimmunity Reviews. 17 (7): 665–673. doi:10.1016/j.autrev.2018.01.017. PMID   29729445. S2CID   19146526.
  5. ↑ Collison LW, Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, et al. (February 2012). "The composition and signaling of the IL-35 receptor are unconventional". Nature Immunology. 13 (3): 290–9. doi:10.1038/ni.2227. PMC   3529151 . PMID   22306691.
  6. ↑ Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. (June 2014). "Interleukin-35 induces regulatory B cells that suppress autoimmune disease". Nature Medicine. 20 (6): 633–41. doi:10.1038/nm.3554. PMC   4048323 . PMID   24743305.
  7. ↑ Devergne O, Hummel M, Koeppen H, Le Beau MM, Nathanson EC, Kieff E, Birkenbach M (February 1996). "A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes". Journal of Virology. 70 (2): 1143–53. doi:10.1128/JVI.70.2.1143-1153.1996. PMC   189923 . PMID   8551575.
  8. 1 2 Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, et al. (March 2014). "IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases". Nature. 507 (7492): 366–370. Bibcode:2014Natur.507..366S. doi:10.1038/nature12979. PMC   4260166 . PMID   24572363.
  9. ↑ Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG (December 2012). "Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade". Journal of Immunology. 189 (12): 5590–601. doi:10.4049/jimmunol.1201744. PMC   3735346 . PMID   23152566.
  10. ↑ Li X, Shao Y, Sha X, Fang P, Kuo YM, Andrews AJ, et al. (March 2018). "IL-35 (Interleukin-35) Suppresses Endothelial Cell Activation by Inhibiting Mitochondrial Reactive Oxygen Species-Mediated Site-Specific Acetylation of H3K14 (Histone 3 Lysine 14)". Arteriosclerosis, Thrombosis, and Vascular Biology. 38 (3): 599–609. doi:10.1161/ATVBAHA.117.310626. PMC   5823772 . PMID   29371247.
  11. ↑ Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, et al. (March 2012). "IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines". PLOS ONE. 7 (3): e33628. Bibcode:2012PLoSO...733628L. doi: 10.1371/journal.pone.0033628 . PMC   3306427 . PMID   22438968.
  12. ↑ Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB, Liew FY (November 2007). "IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells". European Journal of Immunology. 37 (11): 3021–9. doi:10.1002/eji.200737810. PMID   17874423. S2CID   38306559.
  13. ↑ Wu S, Li Y, Li Y, Yao L, Lin T, Jiang S, et al. (May 2016). "Interleukin-35 attenuates collagen-induced arthritis through suppression of vascular endothelial growth factor and its receptors". International Immunopharmacology. 34: 71–77. doi:10.1016/j.intimp.2016.02.018. PMID   26922678.
  14. ↑ Wu S, Li Y, Yao L, Li Y, Jiang S, Gu W, et al. (March 2018). "Interleukin-35 inhibits angiogenesis through STAT1 signalling in rheumatoid synoviocytes". Clinical and Experimental Rheumatology. 36 (2): 223–227. PMID   28850026.
  15. ↑ Vignali DA, Kuchroo VK (July 2012). "IL-12 family cytokines: immunological playmakers". Nature Immunology. 13 (8): 722–8. doi:10.1038/ni.2366. PMC   4158817 . PMID   22814351.
  16. ↑ Sun L, He C, Nair L, Yeung J, Egwuagu CE (October 2015). "Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease". Cytokine. 75 (2): 249–55. doi:10.1016/j.cyto.2015.01.030. PMC   4553122 . PMID   25796985.
  17. ↑ Singh K, Kadesjö E, Lindroos J, Hjort M, Lundberg M, Espes D, et al. (July 2015). "Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells". Scientific Reports. 5 (1): 12633. Bibcode:2015NatSR...512633S. doi:10.1038/srep12633. PMC   4519737 . PMID   26224624.
  18. ↑ Espes D, Singh K, Sandler S, Carlsson PO (August 2017). "Increased Interleukin-35 Levels in Patients With Type 1 Diabetes With Remaining C-Peptide". Diabetes Care. 40 (8): 1090–1095. doi: 10.2337/dc16-2121 . PMID   28620093. S2CID   207367998.
  19. ↑ Tao NN, Gong R, Chen X, He L, Ren F, Yu HB, et al. (May 2018). "Interleukin-35 stimulates hepatitis B virus transcription and replication by targeting transcription factor HNF4α". The Journal of General Virology. 99 (5): 645–654. doi: 10.1099/jgv.0.001050 . PMID   29561254.
  20. ↑ Sawant DV, Hamilton K, Vignali DA (July 2015). "Interleukin-35: Expanding Its Job Profile". Journal of Interferon & Cytokine Research. 35 (7): 499–512. doi:10.1089/jir.2015.0015. PMC   4507123 . PMID   25919641.
  21. ↑ Wu H, Li P, Shao N, Ma J, Ji M, Sun X, et al. (May 2012). "Aberrant expression of Treg-associated cytokine IL-35 along with IL-10 and TGF-β in acute myeloid leukemia". Oncology Letters. 3 (5): 1119–1123. doi:10.3892/ol.2012.614. PMC   3389635 . PMID   22783403.
  22. ↑ Jin P, Ren H, Sun W, Xin W, Zhang H, Hao J (January 2014). "Circulating IL-35 in pancreatic ductal adenocarcinoma patients". Human Immunology. 75 (1): 29–33. doi:10.1016/j.humimm.2013.09.018. PMID   24121041.
  23. ↑ Zeng JC, Zhang Z, Li TY, Liang YF, Wang HM, Bao JJ, et al. (2013-08-15). "Assessing the role of IL-35 in colorectal cancer progression and prognosis". International Journal of Clinical and Experimental Pathology. 6 (9): 1806–16. PMC   3759487 . PMID   24040445.
  24. ↑ Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, Eftekharsadat AT, Sadighi Moghaddam B, Salek Farrokhi A (February 2021). "Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients". Cytokine. 138: 155351. doi:10.1016/j.cyto.2020.155351. ISSN   1043-4666. PMID   33127257. S2CID   226218796.
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