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-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] 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]
As IL-11 over expression is associated with a number of cancers, inhibition of its signaling pathway may have utility in treating cancer.[21]
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.[22]
It is also under investigation as a way to allow
diabetes-damaged kidney tissue to regenerate.[23]
^
abXu 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.
PMID26826523.
^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.
PMID25917632.
Yang YC, Yin T (December 1992). "Interleukin-11 and its receptor". BioFactors. 4 (1): 15–21.
PMID1292471.
Bhatia M, Davenport V, Cairo MS (January 2007). "The role of interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with solid tumors, lymphoma, acute myeloid leukemia and bone marrow failure syndromes". Leukemia & Lymphoma. 48 (1): 9–15.
doi:
10.1080/10428190600909115.
PMID17325843.
S2CID43024459.
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.
PMID1386338.
Yamaguchi M, Miki N, Ono M, Ohtsuka C, Demura H, Kurachi H, Inoue M, Endo H, Taga T, Kishimoto T (March 1995). "Inhibition of growth hormone-releasing factor production in mouse placenta by cytokines using gp130 as a signal transducer". Endocrinology. 136 (3): 1072–8.
doi:
10.1210/endo.136.3.7867561.
PMID7867561.
Morris JC, Neben S, Bennett F, Finnerty H, Long A, Beier DR, Kovacic S, McCoy JM, DiBlasio-Smith E, La Vallie ER, Caruso A, Calvetti J, Morris G, Weich N, Paul SR, Crosier PS, Turner KJ, Wood CR (October 1996). "Molecular cloning and characterization of murine interleukin-11". Experimental Hematology. 24 (12): 1369–76.
PMID8913282.
Curti A, Tafuri A, Ricciardi MR, Tazzari P, Petrucci MT, Fogli M, Ratta M, Lapalombella R, Ferri E, Tura S, Baccarani M, Lemoli RM (April 2002). "Interleukin-11 induces proliferation of human T-cells and its activity is associated with downregulation of p27(kip1)". Haematologica. 87 (4): 373–80.
PMID11940481.
Van der Meeren A, Mouthon MA, Gaugler MH, Vandamme M, Gourmelon P (June 2002). "Administration of recombinant human IL11 after supralethal radiation exposure promotes survival in mice: interactive effect with thrombopoietin". Radiation Research. 157 (6): 642–9.
doi:
10.1667/0033-7587(2002)157[0642:AORHIA]2.0.CO;2.
PMID12005542.
S2CID21496463.