Biology:Interleukin 40

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Short description: Mammalian cytokine


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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.[2] IL-40 is involved in immunoglobulin A (IgA) production, and plays an important role in humoral immune responses and B cell homeostasis and development.[3][4]

Discovery, genes and expression

In October 2017, an article was published[5] concerning a previously uncharacterized gene C17orf99 (chromosome 17 open reading frame 99) which is localized on chromosome 17 (17q25.3).[6] 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.[3]

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.[5]

Function

IL-40 has been found is crucial for humoral immune reactions, synthesis of IgA[7] 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.

Clinical significance

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,[8] several cell lines of human diffuse large B cell lymphoma and also can play some role in autoimmune hepatitis as discriminating autoantigens.[2]

In a disorder called ankylosing spondylitis (AS),[9] 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.[10][11][12]

Rheumatoid Arthritis (RA)

Given the association of IL-40 with B cells homeostasis[13] and the crucial role of B cells in autoimmunity,[13] 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.[14]

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.[13] RA is characterized by autoimmune reactions primarily targeting the synovial membrane,[15] 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.[13] Neutrophils, in particular, have been identified as a known source of IL-40 in the context of RA.[13]

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.[13][14]

IL-40 in RA patients is correlated with disease activity and the levels of autoantibodies.[13] 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.[14] 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 [13]

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.[13][14]

Ankylosing Spondylitis (AS)

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.[16] IL-40 levels were upregulated in serum of AS patients regardless of age, disease duration, disease activity or HLA-B27.[16] This observation is relevant to AS since it is suggested that the gut microbiota plays a role in the development of the condition.[16]

Type 2 Diabetes Mellitus

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.[17]

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.[17] 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.[17]

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.[17] 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.[17]

Sjögren syndrome

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.[18] The expression of IL-40 was associated with the degree of inflammatory infiltrate in the salivary glands,[18] 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.[18] In comparison to nSS patients, CD19+ B lymphocytes were the major source of IL-40 in the lymphatic-infiltrated glands of pSS patients.[18] Furthermore, pSS patients had an expanded population of CD19+IL-40+ B cells in peripheral blood mononuclear cells compared to HCs.[18]

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.[18]

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.[18] Moreover, recombinant IL-40 stimulated NETosis in neutrophils from pSS patients.[18]

References

  1. ↑ Zlotnik, Albert (2020-05-15). "Perspective: Insights on the Nomenclature of Cytokines and Chemokines". Frontiers in Immunology 11: 908. doi:10.3389/fimmu.2020.00908. ISSN 1664-3224. PMID 32499780. 
  2. ↑ 2.0 2.1 Zingaretti, Chiara; Arigò, Milena; Cardaci, Angela; Moro, Monica; Crosti, Mariacristina; Sinisi, Antonella; Sugliano, Elisa; Cheroni, Cristina et al. (December 2012). "Identification of New Autoantigens by Protein Array Indicates a Role for IL4 Neutralization in Autoimmune Hepatitis" (in en). Molecular & Cellular Proteomics 11 (12): 1885–1897. doi:10.1074/mcp.M112.018713. PMID 22997428. 
  3. ↑ 3.0 3.1 Catalan-Dibene, Jovani; McIntyre, Laura L.; Zlotnik, Albert (October 2018). "Interleukin 30 to Interleukin 40" (in en). Journal of Interferon & Cytokine Research 38 (10): 423–439. doi:10.1089/jir.2018.0089. ISSN 1079-9907. PMID 30328794. 
  4. ↑ Mertowska, Paulina; Mertowski, Sebastian; Smarz-Widelska, Iwona; Grywalska, Ewelina (2022-01-07). "Biological Role, Mechanism of Action and the Importance of Interleukins in Kidney Diseases" (in en). International Journal of Molecular Sciences 23 (2): 647. doi:10.3390/ijms23020647. ISSN 1422-0067. PMID 35054831. 
  5. ↑ 5.0 5.1 Catalan-Dibene, Jovani; Vazquez, Monica I.; Luu, Van Phi; Nuccio, Sean-Paul; Karimzadeh, Alborz; Kastenschmidt, Jenna M.; Villalta, S. Armando; Ushach, Irina et al. (2017-11-01). "Identification of IL-40, a Novel B Cell–Associated Cytokine" (in en). The Journal of Immunology 199 (9): 3326–3335. doi:10.4049/jimmunol.1700534. ISSN 0022-1767. PMID 28978694. PMC 5667921. https://journals.aai.org/jimmunol/article/199/9/3326/109831/Identification-of-IL-40-a-Novel-B-Cell-Associated. 
  6. ↑ Zhang, Chengxin; Wei, Xiaoqiong; Omenn, Gilbert S.; Zhang, Yang (2018-12-07). "Structure and Protein Interaction-Based Gene Ontology Annotations Reveal Likely Functions of Uncharacterized Proteins on Human Chromosome 17" (in en). Journal of Proteome Research 17 (12): 4186–4196. doi:10.1021/acs.jproteome.8b00453. ISSN 1535-3893. PMID 30265558. 
  7. ↑ McGhee, Jerry R.; Mestecky, Jiri; Elson, Charles O.; Kiyono, Hiroshi (May 1989). "Regulation of IgA synthesis and immune response by T cells and interleukins" (in en). Journal of Clinical Immunology 9 (3): 175–199. doi:10.1007/BF00916814. ISSN 0271-9142. PMID 2671008. http://link.springer.com/10.1007/BF00916814. 
  8. ↑ Nussrat, Shahad W.; Ad'hiah, Ali H. (January 2023). "Interleukin-40 is a promising biomarker associated with type 2 diabetes mellitus risk" (in en). Immunology Letters: S0165247823000068. doi:10.1016/j.imlet.2023.01.006. PMID 36640967. https://linkinghub.elsevier.com/retrieve/pii/S0165247823000068. 
  9. ↑ Hreggvidsdottir, Hulda S.; Noordenbos, Troy; Baeten, Dominique L. (2014-01-01). "Inflammatory pathways in spondyloarthritis" (in en). Molecular Immunology. The pathogenesis of ankylosing spondylitis: HLA-B27 and beyond 57 (1): 28–37. doi:10.1016/j.molimm.2013.07.016. ISSN 0161-5890. PMID 23969080. https://www.sciencedirect.com/science/article/pii/S0161589013004823. 
  10. ↑ Sveaas, Sh; Berg, Ij; Provan, Sa; Semb, Ag; Olsen, Ic; Ueland, T; Aukrust, P; Vøllestad, N et al. (2015-03-04). "Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study" (in en). Scandinavian Journal of Rheumatology 44 (2): 118–124. doi:10.3109/03009742.2014.956142. ISSN 0300-9742. PMID 25756521. http://www.tandfonline.com/doi/full/10.3109/03009742.2014.956142. 
  11. ↑ Yang, Meng-Ge; Tian, Suyan; Zhang, Qingxiang; Han, Jinming; Liu, Caiyun; Zhou, Yang; Zhu, Jie; Jin, Tao (November 2020). "Elevated serum interleukin-39 levels in patients with neuromyelitis optica spectrum disorders correlated with disease severity" (in en). Multiple Sclerosis and Related Disorders 46: 102430. doi:10.1016/j.msard.2020.102430. PMID 32853892. https://linkinghub.elsevier.com/retrieve/pii/S2211034820305058. 
  12. ↑ Russell, S. E.; Horan, R. M.; Stefanska, A. M.; Carey, A.; Leon, G.; Aguilera, M.; Statovci, D.; Moran, T. et al. (2016-09-01). "IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation" (in en). Mucosal Immunology 9 (5): 1193–1204. doi:10.1038/mi.2015.134. ISSN 1933-0219. PMID 26813344. https://www.sciencedirect.com/science/article/pii/S1933021922007668. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 Navrátilová, A., Andrés Cerezo, L., Hulejova, H., Bečvář, V., Tomčík, M., Komarc, M., ... & Šenolt, L. (2021). IL-40: A New B Cell-Associated Cytokine Up-Regulated in Rheumatoid Arthritis Decreases Following the Rituximab Therapy and Correlates With Disease Activity, Autoantibodies, and NETosis. Frontiers in Immunology, 12, 745523.
  14. ↑ 14.0 14.1 14.2 14.3 Navrátilová, A., Bečvář, V., Hulejová, H., Tomčík, M., Štolová, L., Mann, H., ... & Cerezo, L. A. (2023). New pro-inflammatory cytokine IL-40 is produced by activated neutrophils and plays a role in the early stages of seropositive rheumatoid arthritis. RMD open, 9(2), e002894.
  15. ↑ Scherer, H. U., Häupl, T., & Burmester, G. R. (2020). The etiology of rheumatoid arthritis. Journal of autoimmunity, 110, 102400.
  16. ↑ 16.0 16.1 16.2 Jaber, A. S., & Ad'hiah, A. H. (2023). A novel signature of interleukins 36α, 37, 38, 39 and 40 in ankylosing spondylitis. Cytokine, 162, 156117..
  17. ↑ 17.0 17.1 17.2 17.3 17.4 Nussrat SW, Ad'hiah AH. Interleukin-40 is a promising biomarker associated with type 2 diabetes mellitus risk. Immunol Lett. 2023 Feb;254:1-5. doi: 10.1016/j.imlet.2023.01.006. Epub 2023 Jan 11. PMID 36640967.
  18. ↑ 18.0 18.1 18.2 18.3 18.4 18.5 18.6 18.7 Guggino G, Rizzo C, Mohammadnezhad L, Lo Pizzo M, Lentini VL, Di Liberto D, La Barbera L, Raimondo S, Shekarkar Azgomi M, Urzì O, Berardicurti O, Campisi G, Alessandro R, Giacomelli R, Dieli F, Ciccia F. Possible role for IL-40 and IL-40-producing cells in the lymphocytic infiltrated salivary glands of patients with primary Sjögren's syndrome. RMD Open. 2023 May;9(2):e002738. doi: 10.1136/rmdopen-2022-002738. PMID 37137540; PMCID: PMC10163598.



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