Interleukin 11

Last updated

IL11
Human IL-11 crystal structure.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL11 , AGIF, IL-11, interleukin 11
External IDs OMIM: 147681; MGI: 107613; HomoloGene: 535; GeneCards: IL11; OMA:IL11 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3589

16156

Ensembl

ENSG00000095752

ENSMUSG00000004371

UniProt

P20809

P47873

RefSeq (mRNA)

NM_001267718
NM_000641

NM_008350
NM_001290423

RefSeq (protein)

NP_000632
NP_001254647

NP_001277352
NP_032376

Location (UCSC) Chr 19: 55.36 – 55.37 Mb Chr 7: 4.78 – 4.79 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interleukin 11 (IL-11 or adipogenesis inhibitory factor [5] ) is a protein that in humans is encoded by the IL11 gene. [6]

Contents

IL-11 is a cytokine that was first isolated in 1990 from bone marrow-derived fibrocyte-like stromal cells. It was initially thought to be important for hematopoiesis, notably for megakaryocyte maturation, [7] but subsequently shown to be redundant for platelets, and for other blood cell types, in both mice and humans. [8] [9] It was developed as a recombinant protein (rhIL-11) as the drug substance oprelvekin.

The human IL-11 gene, consisting of 5 exons and 4 introns, is located on chromosome 19, [6] and encodes a 23 kDa protein. IL-11 is a member of the IL-6-type cytokine family, distinguished based on their use of the common co-receptor gp130. Signal specificity is provided by the IL-11Rα subunit which is expressed at high levels in fibroblasts and other stromal cells but not immune cells, unlike IL6 receptors that are expressed at highest levels in immune cells and lowly expressed in stromal cells. [10]

Downstream signalling

Signal transduction is initiated upon binding of IL-11 to IL-11Rα and gp130, facilitating the formation of higher order structures involving dimers of gp130:Il-11:Il11RA complexes. In some instances, in epithelial-derived cells and cancer cell lines, this permits gp130-associated Janus kinases (JAK) activation and downstream STAT-mediated transcriptional activities. [11] In other instances, in stromal cells, IL-11 activates non-canonical MAPK/ERK-dependent signalling to initiate the post-transcriptional upregulation of specific subsets of transcripts in the absence of an effect on transcription. [10] In fibroblasts, IL-11 drives an ERK-dependent autocrine loop of fibrogenic protein synthesis that is at a nexus of fibrotic signalling and required for the pro-fibrotic activity of TGFB1, PDGF, endothelin1, angiotensin and many other pro-fibrotic factors. [10] IL-11 has also been described in various aspects of tissue regeneration, predominantly in regenerative species like the zebrafish or the axolotl. [12] [13] Here, activation of STAT3 by IL-11 is mandatory to allow regeneration and to prevent injury-induced fibrotic remodeling and scar formation. [14]

Function

IL-11 through its binding to its transmembrane IL-11Rα receptor and resultant activation of downstream signaling pathways has been thought to regulate adipogenesis, osteoclastogenesis, neurogenesis and platelet maturation. [15] More recently it has been discovered that over-expression of IL-11 is associated with a variety of cancers and may provide a link between inflammation and cancer. [15]

IL-11 has been demonstrated to improve platelet recovery after chemotherapy-induced thrombocytopenia, induce acute phase proteins, modulate antigen-antibody responses, participate in the regulation of bone cell proliferation and differentiation IL-11 causes bone-resorption. It stimulates the growth of certain lymphocytes and, in the murine model, stimulates an increase in the cortical thickness and strength of long bones. In addition to having lymphopoietic/hematopoietic and osteotrophic properties, it has functions in many other tissues, including the brain, gut, testis, kidney and bone. [16]

As a signaling molecule, interleukin 11 has a variety of functions associated with its receptor interleukin 11 receptor alpha; such functions include placentation and to some extent decidualization. [17] IL11 has a role during blastocyst implantation in the uteral endometrium; as the blastocyst is imbedded within the endometrium, extravillous trophoblasts invade the maternal spiral arteries for stability and the transfer of life-sustaining elements via the maternal and fetal circulatory systems. This process is highly regulated due to detrimental consequences that can arise from aberrations of the placentation process: poor infiltration of trophoblasts may result in preeclampsia, while severely invasive trophoblasts may resolve in placenta accreta, increta or percreta; all defects that most likely would result in the early demise of the embryo and/or negative effects upon the mother. [17] IL11 is present in the decidua and chorionic villi to regulate the extent in which the placenta implants itself; regulations to ensure maternal well-being and the growth and survival of the fetus. A murine knockout model has been produced for this particular gene, with initial studies involving IL11 role in bone pathologies but have since progressed to fertility research; further research utilizes endometrial and gestational tissue from humans. [17] [18]

Manufacture

Interleukin 11 is manufactured using recombinant DNA technology.[ citation needed ]

Therapeutic target

A recombinant form of IL-11, oprelvekin, is a protein therapeutic used for the prevention of severe thrombocytopenia in cancer patients. [19] [20]

As IL-11 over-expression is associated with a number of cancers, inhibition of its signaling pathway may have utility in treating cancer, [21] and has also been researched for its potential ability to slow down aging. [22] [23]

Transforming growth factor β1 (TGFβ1) through up-regulation of IL-11, stimulates collagen production and is important in wound healing. However dysregulation of TGFβ1 and downstream IL-11 is associated with fibrotic diseases hence inhibition of IL-11 may have utility in treating fibrosis. [10] This cytokine promotes recruitment of immune suppressive cancer-associated fibroblasts to tumors and facilitates chemoresistance. [24]

It is also under investigation as a way to allow diabetes-damaged kidney tissue to regenerate. [25]

See also

Related Research Articles

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

Cytokines (/'saɪ.tə.kaɪn/) 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 6</span> Cytokine protein

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

<span class="mw-page-title-main">Interleukin 7</span> Growth factor secreted by stromal cells in the bone marrow and thymus.

Interleukin 7 (IL-7) is a protein that in humans is encoded by the IL7 gene.

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

Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.

<span class="mw-page-title-main">Interleukin 31</span>

Interleukin-31 (IL-31) is a protein that in humans is encoded by the IL31 gene that resides on chromosome 12. IL-31 is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronic inflammatory diseases, including atopic dermatitis.

<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 22</span> Protein, encoded in humans by IL22 gene

Interleukin-22 (IL-22) is a protein that in humans is encoded by the IL22 gene.

<span class="mw-page-title-main">Glycoprotein 130</span> Mammalian protein found in Homo sapiens

Glycoprotein 130 is a transmembrane protein which is the founding member of the class of tall cytokine receptors. It forms one subunit of the type I cytokine receptor within the IL-6 receptor family. It is often referred to as the common gp130 subunit, and is important for signal transduction following cytokine engagement. As with other type I cytokine receptors, gp130 possesses a WSXWS amino acid motif that ensures correct protein folding and ligand binding. It interacts with Janus kinases to elicit an intracellular signal following receptor interaction with its ligand. Structurally, gp130 is composed of five fibronectin type-III domains and one immunoglobulin-like C2-type (immunoglobulin-like) domain in its extracellular portion.

<span class="mw-page-title-main">Interleukin-1 receptor antagonist</span> Protein and coding gene in humans

The interleukin-1 receptor antagonist (IL-1RA) is a protein that in humans is encoded by the IL1RN gene.

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

Oncostatin-M specific receptor subunit beta also known as the Oncostatin M receptor (OSMR), is one of the receptor proteins for oncostatin M, that in humans is encoded by the OSMR gene.

<span class="mw-page-title-main">Interleukin-6 receptor</span> Protein-coding gene in the species Homo sapiens

Interleukin 6 receptor (IL6R) also known as CD126 is a type I cytokine receptor.

<span class="mw-page-title-main">Interleukin 1 receptor, type II</span> Protein-coding gene in the species Homo sapiens

Interleukin 1 receptor, type II (IL-1R2) also known as CD121b is an interleukin receptor. IL1R2 also denotes its human gene.

<span class="mw-page-title-main">Colony stimulating factor 1 receptor</span> Protein found in humans

Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115, is a cell-surface protein encoded by the human CSF1R gene. CSF1R is a receptor that can be activated by two ligands: colony stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells, and CSF1R signaling is necessary for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and inflammatory bone diseases.

<span class="mw-page-title-main">Interleukin 1 receptor, type I</span> Type of interleukin receptor

Interleukin 1 receptor, type I (IL1R1) also known as CD121a, is an interleukin receptor. IL1R1 also denotes its human gene.

<span class="mw-page-title-main">Interleukin 11 receptor alpha subunit</span> Protein-coding gene in the species Homo sapiens

Interleukin 11 receptor, alpha subunit is a subunit of the interleukin 11 receptor. IL11RA is its human gene.

<span class="mw-page-title-main">IL17RA</span> Protein-coding gene in the species Homo sapiens

Interleukin 17 receptor A, also known as IL17RA and CDw217, is a human 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.

<span class="mw-page-title-main">Olamkicept</span> Chemical compound

Olamkicept, also known as soluble gp130Fc or sgp130Fc is an immunosuppressive drug candidate, which selectively blocks activities of the cytokine Interleukin-6, which are mediated by the soluble Interleukin-6. Interleukin-6 is a cytokine, which plays a dominant role in the regulation of the immune response and also in autoimmunity. Furthermore, Interleukin-6 has been demonstrated to be involved in the regulation of metabolism and body weight. Interleukin-6 also has many activities on neural cells. The biochemical principle was invented by the German biochemist Stefan Rose-John and it was further developed into a biotech compound by the Conaris Research Institute AG, which gave an exclusive world-wide license to the Swiss-based biopharmaceutical company Ferring Pharmaceuticals. In December 2016, Ferring and the biotech company I-MAB signed a licensing agreement granting I-MAB exclusive rights in Asia to Olamkicept for the treatment of autoimmune disease.

Hyper-IL-6 is a designer cytokine, which was generated by the German biochemist Stefan Rose-John. Hyper-IL-6 is a fusion protein of the four-helical cytokine Interleukin-6 and the soluble Interleukin-6 receptor which are covalently linked by a flexible peptide linker. Interleukin-6 on target cells binds to a membrane bound Interleukin-6 receptor. The complex of Interleukin-6 and the Interleukin-6 receptor associate with a second receptor protein called gp130, which dimerises and initiates intracellular signal transduction. Gp130 is expressed on all cells of the human body whereas the Interleukin-6 receptor is only found on few cells such as hepatocytes and some leukocytes. Neither Interleukin-6 nor the Interleukin-6 receptor have a measurable affinity for gp130. Therefore, cells, which only express gp130 but no Interleukin-6 receptor are not responsive to Interleukin-6. It was found, however, that the membrane-bound Interleukin-6 receptor can be cleaved from the cell membrane generating a soluble Interleukin-6 receptor. The soluble Interleukin-6 receptor can bind the ligand Interleukin-6 with similar affinity as the membrane-bound Interleukin-6 receptor and the complex of Interleukin-6 and the soluble Interleukin-6 receptor can bind to gp130 on cells, which only express gp130 but no Interleukin-6 receptor. The mode of signaling via the soluble Interleukin-6 receptor has been named Interleukin-6 trans-signaling whereas Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is referred to as Interleukin-6 classic signaling. Therefore, the generation of the soluble Interleukin-6 receptor enables cells to respond to Interleukin-6, which in the absence of soluble Interleukin-6 receptor would be completely unresponsive to the cytokine.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000095752 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000004371 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Kawashima I, Ohsumi J, Mita-Honjo K, Shimoda-Takano K, Ishikawa H, Sakakibara S, et al. (June 1991). "Molecular cloning of cDNA encoding adipogenesis inhibitory factor and identity with interleukin-11". FEBS Letters. 283 (2): 199–202. doi: 10.1016/0014-5793(91)80587-S . PMID   1828438. S2CID   1385397.
  6. 1 2 McKinley D, Wu Q, Yang-Feng T, Yang YC (July 1992). "Genomic sequence and chromosomal location of human interleukin-11 gene (IL11)". Genomics. 13 (3): 814–9. doi:10.1016/0888-7543(92)90158-O. PMID   1386338.
  7. ↑ Paul SR, Bennett F, Calvetti JA, Kelleher K, Wood CR, O'Hara RM, et al. (October 1990). "Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine". Proceedings of the National Academy of Sciences of the United States of America. 87 (19): 7512–6. Bibcode:1990PNAS...87.7512P. doi: 10.1073/pnas.87.19.7512 . PMC   54777 . PMID   2145578.
  8. ↑ Nandurkar HH, Robb L, Tarlinton D, Barnett L, Köntgen F, Begley CG (September 1997). "Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis". Blood. 90 (6): 2148–59. doi: 10.1182/blood.V90.6.2148 . PMID   9310465.
  9. ↑ Brischoux-Boucher E, Trimouille A, Baujat G, Goldenberg A, Schaefer E, Guichard B, et al. (October 2018). "IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences". Clinical Genetics. 94 (3–4): 373–380. doi:10.1111/cge.13409. PMID   29926465. S2CID   49339003.
  10. 1 2 3 4 Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, et al. (December 2017). "IL-11 is a crucial determinant of cardiovascular fibrosis". Nature. 552 (7683): 110–115. Bibcode:2017Natur.552..110S. doi:10.1038/nature24676. hdl:10044/1/54929. PMC   5807082 . PMID   29160304.
  11. ↑ Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (August 2003). "Principles of interleukin (IL)-6-type cytokine signalling and its regulation". The Biochemical Journal. 374 (Pt 1): 1–20. doi:10.1042/BJ20030407. PMC   1223585 . PMID   12773095.
  12. ↑ Gerber T, Murawala P, Knapp D, Masselink W, Schuez M, Hermann S, et al. (October 2018). "Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration". Science. 362 (6413): eaaq0681. Bibcode:2018Sci...362..681G. doi:10.1126/science.aaq0681. PMC   6669047 . PMID   30262634.
  13. ↑ Allanki S, Strilic B, Scheinberger L, Onderwater YL, Marks A, Günther S, et al. (September 2021). "Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration". Science Advances. 7 (37): eabg6497. Bibcode:2021SciA....7.6497A. doi:10.1126/sciadv.abg6497. PMC   8442930 . PMID   34516874.
  14. ↑ Allanki S, Strilic B, Scheinberger L, Onderwater YL, Marks A, Günther S, et al. (September 2021). "Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration". Science Advances. 7 (37): eabg6497. Bibcode:2021SciA....7.6497A. doi:10.1126/sciadv.abg6497. PMC   8442930 . PMID   34516874.
  15. 1 2 Xu DH, Zhu Z, Wakefield MR, Xiao H, Bai Q, Fang Y (April 2016). "The role of IL-11 in immunity and cancer". Cancer Letters. 373 (2): 156–63. doi:10.1016/j.canlet.2016.01.004. PMID   26826523.
  16. ↑ Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, et al. (July 2005). "Interleukin-11 receptor signaling is required for normal bone remodeling". Journal of Bone and Mineral Research. 20 (7): 1093–102. doi: 10.1359/JBMR.050209 . PMID   15940362. S2CID   23648686.
  17. 1 2 3 Paiva P, Salamonsen LA, Manuelpillai U, Walker C, Tapia A, Wallace EM, et al. (November 2007). "Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation". Endocrinology. 148 (11): 5566–72. doi: 10.1210/en.2007-0517 . PMID   17702845.
  18. ↑ Chen HF, Lin CY, Chao KH, Wu MY, Yang YS, Ho HN (May 2002). "Defective production of interleukin-11 by decidua and chorionic villi in human anembryonic pregnancy". The Journal of Clinical Endocrinology and Metabolism. 87 (5): 2320–8. doi: 10.1210/jc.87.5.2320 . PMID   11994383.
  19. ↑ Sitaraman SV, Gewirtz AT (October 2001). "Oprelvekin. Genetics Institute". Current Opinion in Investigational Drugs. 2 (10): 1395–400. PMID   11890354.
  20. ↑ "Oprelvekin Injection". RxList.
  21. ↑ Putoczki TL, Ernst M (2015). "IL-11 signaling as a therapeutic target for cancer". Immunotherapy. 7 (4): 441–53. doi:10.2217/imt.15.17. PMID   25917632.
  22. ↑ Widjaja AA, Lim WW, Viswanathan S, Chothani S, Corden B, Dasan CM, et al. (July 2024). "Inhibition of IL-11 signalling extends mammalian healthspan and lifespan". Nature. doi: 10.1038/s41586-024-07701-9 . PMC   11291288 . PMID   39020175.
  23. ↑ Ledford H (2024-07-17). "Mice live longer when inflammation-boosting protein is blocked". Nature. 631 (8022): 716–717. doi:10.1038/d41586-024-02298-5.
  24. ↑ Tao L, Huang G, Wang R, Pan Y, He Z, Chu X, et al. (December 2016). "Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway". Scientific Reports. 6: 38408. Bibcode:2016NatSR...638408T. doi:10.1038/srep38408. PMC   5138853 . PMID   27922075.
  25. ↑ Irving M (2023-02-13). "Scientists regenerate kidneys to reverse diabetes damage in mice". New Atlas. Retrieved 2023-02-13.

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