Interleukin-11 Signaling Pathway (Homo sapiens)

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IL-11 is a multifunctional cytokine that belongs to the gp130 family. It was first isolated from a primate bone marrow derived cell line, PU-34 for its ability to stimulate the proliferation of a plasmacytoma cell line, T1165 which was dependent on IL-6. This cytokine plays an important role in the synthesis, maturation and differentiation of hematopoietic cells. It also plays significant role in the inhibition of adipocyte differentiation, regulation of trophoblasts invasion and placentation in humans.

The receptor for IL-11 is IL11RA that uses the common gp130 receptor subunit for signal transduction. The pathways that are activated upon IL-11 stimulation are JAK-STAT, Ras-MAPK, PI3K-AKT and NF-kappa B/p65. Binding of IL-11 with IL-11RA results in the heterodimerization, tyrosine phosphorylation and activation of gp130. The activated IL11RA-gp130 receptor complex further activates Jak family of tyrosine kinases, JAK1 and JAK2. Phosphorylated JAK2 then activates STAT3 and STAT1 that results in their subsequent translocation into the nucleus. The translocated STAT3 then induces the transcription of genes associated with endometrial cell adhesion, gastric inflammation and differentiation of periodontal ligament cells. The activation of STAT3 was shown to be inhibited by the overexpression of Suppressor of cytokine signalling 3 (SOCS3). IL-11 signalling through JAK2/STAT3 has been shown to be crucial for normal placentation in humans and normal development of craniofacial bones and teeth in mice.

In addition to JAK-STAT, IL-11 also activate the Ras-MAPK, PI3K-AKT and NF-kappa B pathways. In response to IL-11, GTP loaded Ras interacts with RAF1 and leads to autophosphorylation of RAF1. Activation of RAF1 leads to the tyrosine phosphorylation and activation of mitogen activated protein kinases (MAPKs) through MEK1 and MEK2. Activation of phospholipase D was triggered by IL-11 leading to the formation of phosphatidic acid, which has also been shown to activate the MAPKs. Transcription factors, ATF1 and CREB1 were activated by these phosphorylated MAPKs through p90 S6 kinase. PI3K-AKT and NF-kappa B/p65 pathways stimulated by IL-11 have been shown to enhance the migration and proliferation of chondrosarcoma cells. In CD4+ T cells, Th2 polarization was induced by IL-11 through NF-kappa B inhibition. SRC, FYN and YES, members of Src family of tyrosine kinases were also activated in response to IL-11 signalling.

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