Interleukin 11

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

IL11
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIL11, AGIF, IL-11, interleukin 11
External IDsOMIM: 147681 MGI: 107613 HomoloGene: 535 GeneCards: IL11
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 MbChr 7: 4.78 – 4.79 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

IL-11 is a cytokine and 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,[6] but subsequently shown to be redundant for platelets, and for other blood cell types, in both mice and humans.[7][8] It is also known under the names adipogenesis inhibitory factor (AGIF)[9] and 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.[10]

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.[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]

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.[12] 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.[12]

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 and bone.[13]

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 of decidualization.[14] IL11 has been expressed to have a role during implantation of the blastocyst in the endometrium of the uterus; as the blastocyst is imbedded within the endometrium, the extravillous trophoblasts will invade the maternal spiral arteries for stability and the transfer of essential 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 the trophoblasts may result in preeclampsia while severely invasive trophoblasts may resolve in placenta accreta, increta or percreta; all defects which most likely would result in the early demise of the embryo and/or negative effects upon the mother.[14] IL11 has been shown to be present in the decidua and chorionic villi to regulate the extent in which the placenta implants itself; regulations to ensure the well-being of the mother but also the normal 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.[14][15]

Medical use

Interleukin 11 is manufactured using recombinant DNA technology and is marketed as a protein therapeutic called oprelvekin, for the prevention of severe thrombocytopenia in cancer patients.[16][17]

As a therapeutic target

As IL-11 over expression is associated with a number of cancers, inhibition of its signaling pathway may have utility in treating cancer.[18]

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] Furthermore, this cytokine has been found to promote recruitment of immune suppressive cancer-associated fibroblasts to tumors and facilitates chemoresistance.[19]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000095752 - Ensembl, May 2017
  2. 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. 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.
  6. Paul SR, Bennett F, Calvetti JA, Kelleher K, Wood CR, O'Hara RM, Leary AC, Sibley B, Clark SC, Williams DA (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.
  7. 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.
  8. 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 (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.
  9. 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. doi:10.1016/0014-5793(91)80587-S. PMID 1828438. S2CID 1385397.
  10. 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. 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.
  13. Sims NA, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ (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.
  14. Paiva P, Salamonsen LA, Manuelpillai U, Walker C, Tapia A, Wallace EM, Dimitriadis E (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.
  15. 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.
  16. Sitaraman SV, Gewirtz AT (October 2001). "Oprelvekin. Genetics Institute". Current Opinion in Investigational Drugs. 2 (10): 1395–400. PMID 11890354.
  17. "Oprelvekin Injection". RxList.
  18. 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.
  19. Tao L, Huang G, Wang R, Pan Y, He Z, Chu X, Song H, Chen L (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.

Further reading
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