Interleukin 11 Explained

Interleukin 11 (IL-11 or adipogenesis inhibitory factor[1]) is a protein that in humans is encoded by the IL11 gene.

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,[2] but subsequently shown to be redundant for platelets, and for other blood cell types, in both mice and humans.[3] [4] 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,[5] 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.[6]

Downstream signalling

Signal transduction is initiated upon binding of IL-11 to IL-11Ralpha 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.[7] 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. 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. IL-11 has also been described in various aspects of tissue regeneration, predominantly in regenerative species like the zebrafish or the axolotl.[8] [9] Here, activation of STAT3 by IL-11 is mandatory to allow regeneration and to prevent injury-induced fibrotic remodeling and scar formation.[10]

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.[11] 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.

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.[12]

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.[13] 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.[13] 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.[13] [14]

Manufacture

Interleukin 11 is manufactured using recombinant DNA technology.

Therapeutic target

A recombinant form of IL-11, oprelvekin, is a protein therapeutic used for the prevention of severe thrombocytopenia in cancer patients.[15] [16]

As IL-11 over-expression is associated with a number of cancers, inhibition of its signaling pathway may have utility in treating cancer,[17] and has also been researched for its potential ability to slow down aging.[18] [19]

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. This cytokine promotes recruitment of immune suppressive cancer-associated fibroblasts to tumors and facilitates chemoresistance.[20]

It is also under investigation as a way to allow diabetes-damaged kidney tissue to regenerate.[21]

See also

Further reading

Notes and References

  1. Kawashima I, Ohsumi J, Mita-Honjo K, Shimoda-Takano K, Ishikawa H, Sakakibara S, Miyadai K, Takiguchi Y . June 1991 . Molecular cloning of cDNA encoding adipogenesis inhibitory factor and identity with interleukin-11 . FEBS Letters . 283 . 2 . 199–202 . 10.1016/0014-5793(91)80587-S . 1828438 . 1385397. free .
  2. Paul SR, Bennett F, Calvetti JA, Kelleher K, Wood CR, O'Hara RM, Leary AC, Sibley B, Clark SC, Williams DA . 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 . October 1990 . 2145578 . 54777 . 10.1073/pnas.87.19.7512 . 1990PNAS...87.7512P . free .
  3. Nandurkar HH, Robb L, Tarlinton D, Barnett L, Köntgen F, Begley CG . Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis . Blood . 90 . 6 . 2148–59 . September 1997 . 10.1182/blood.V90.6.2148 . 9310465 . free .
  4. Brischoux-Boucher E, Trimouille A, Baujat G, Goldenberg A, Schaefer E, Guichard B, Hannequin P, Paternoster G, Baer S, Cabrol C, Weber E, Godfrin G, Lenoir M, Lacombe D, Collet C, Van Maldergem L . IL11RA-related Crouzon-like autosomal recessive craniosynostosis in 10 new patients: Resemblances and differences . Clinical Genetics . 94 . 3–4 . 373–380 . October 2018 . 29926465 . 10.1111/cge.13409 . 49339003 .
  5. McKinley D, Wu Q, Yang-Feng T, Yang YC . Genomic sequence and chromosomal location of human interleukin-11 gene (IL11) . Genomics . 13 . 3 . 814–9 . July 1992 . 1386338 . 10.1016/0888-7543(92)90158-O .
  6. Schafer S, Viswanathan S, Widjaja AA, Lim WW, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, Tan J, Chothani SP, Ye L, Rackham OJ, Ko NS, Sahib NE, Pua CJ, Zhen NT, Xie C, Wang M, Maatz H, Lim S, Saar K, Blachut S, Petretto E, Schmidt S, Putoczki T, Guimarães-Camboa N, Wakimoto H, van Heesch S, Sigmundsson K, Lim SL, Soon JL, Chao VT, Chua YL, Tan TE, Evans SM, Loh YJ, Jamal MH, Ong KK, Chua KC, Ong BH, Chakaramakkil MJ, Seidman JG, Seidman CE, Hubner N, Sin KY, Cook SA . IL-11 is a crucial determinant of cardiovascular fibrosis . Nature . 552 . 7683 . 110–115 . December 2017 . 29160304 . 5807082 . 10.1038/nature24676 . 2017Natur.552..110S . 10044/1/54929 .
  7. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F . Principles of interleukin (IL)-6-type cytokine signalling and its regulation . The Biochemical Journal . 374 . Pt 1 . 1–20 . August 2003 . 12773095 . 1223585 . 10.1042/BJ20030407 .
  8. Gerber T, Murawala P, Knapp D, Masselink W, Schuez M, Hermann S, Gac-Santel M, Nowoshilow S, Kageyama J, Khattak S, Currie JD, Camp JG, Tanaka EM, Treutlein B . Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration . Science . 362 . 6413 . eaaq0681 . October 2018 . 30262634 . 6669047 . 10.1126/science.aaq0681 . 2018Sci...362..681G .
  9. Allanki S, Strilic B, Scheinberger L, Onderwater YL, Marks A, Günther S, Preussner J, Kikhi K, Looso M, Stainier DY, Reischauer S . Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration . Science Advances . 7 . 37 . eabg6497 . September 2021 . 34516874 . 8442930 . 10.1126/sciadv.abg6497 . 2021SciA....7.6497A .
  10. Allanki S, Strilic B, Scheinberger L, Onderwater YL, Marks A, Günther S, Preussner J, Kikhi K, Looso M, Stainier DY, Reischauer S . Interleukin-11 signaling promotes cellular reprogramming and limits fibrotic scarring during tissue regeneration . Science Advances . 7 . 37 . eabg6497 . September 2021 . 34516874 . 10.1126/sciadv.abg6497 . 8442930 . 2021SciA....7.6497A .
  11. Xu DH, Zhu Z, Wakefield MR, Xiao H, Bai Q, Fang Y . The role of IL-11 in immunity and cancer . Cancer Letters . 373 . 2 . 156–63 . April 2016 . 26826523 . 10.1016/j.canlet.2016.01.004 .
  12. Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ . Interleukin-11 receptor signaling is required for normal bone remodeling . Journal of Bone and Mineral Research . 20 . 7 . 1093–102 . July 2005 . 15940362 . 10.1359/JBMR.050209 . 23648686 . free .
  13. Paiva P, Salamonsen LA, Manuelpillai U, Walker C, Tapia A, Wallace EM, Dimitriadis E . Interleukin-11 promotes migration, but not proliferation, of human trophoblast cells, implying a role in placentation . Endocrinology . 148 . 11 . 5566–72 . November 2007 . 17702845 . 10.1210/en.2007-0517 . free .
  14. Chen HF, Lin CY, Chao KH, Wu MY, Yang YS, Ho HN . 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 . May 2002 . 11994383 . 10.1210/jc.87.5.2320 . free .
  15. Sitaraman SV, Gewirtz AT . October 2001 . Oprelvekin. Genetics Institute . Current Opinion in Investigational Drugs . 2 . 10 . 1395–400 . 11890354.
  16. Web site: Oprelvekin Injection . RxList.
  17. Putoczki TL, Ernst M . IL-11 signaling as a therapeutic target for cancer . Immunotherapy . 7 . 4 . 441–53 . 2015 . 25917632 . 10.2217/imt.15.17 .
  18. Widjaja AA, Lim WW, Viswanathan S, Chothani S, Corden B, Dasan CM, Goh JW, Lim R, Singh BK, Tan J, Pua CJ, Lim SY, Adami E, Schafer S, George BL, Sweeney M, Xie C, Tripathi M, Sims NA, Hübner N, Petretto E, Withers DJ, Ho L, Gil J, Carling D, Cook SA . Inhibition of IL-11 signalling extends mammalian healthspan and lifespan . Nature . July 2024 . 39020175 . 10.1038/s41586-024-07701-9 . free . 11291288 .
  19. Ledford . Heidi . 2024-07-17 . Mice live longer when inflammation-boosting protein is blocked . Nature . en . 631 . 8022 . 716–717 . 10.1038/d41586-024-02298-5.
  20. Tao L, Huang G, Wang R, Pan Y, He Z, Chu X, Song H, Chen L . Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway . Scientific Reports . 6 . 38408 . December 2016 . 27922075 . 5138853 . 10.1038/srep38408 . 2016NatSR...638408T .
  21. Web site: Irving M . 2023-02-13 . Scientists regenerate kidneys to reverse diabetes damage in mice . 2023-02-13 . New Atlas . en-US.

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