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One of the most noteworthy aspect of IL-6 signaling is that IL-6 is a pleiotropic cytokine and can elicit a variety of distinct or even contradictory physiopathological processes. This article highlights two most popularly referenced IL-6 signaling pathways, the Classic and Trans-Signaling Pathway of IL-6. IL-6 is a soluble ligand whose receptor IL-6R has two distinct forms. The membrane bound form, mbIL-6R, also called CD126 or gp80, forms a complex with IL-6 and then binds to two molecules of gp130. This binding activates the classic IL-6 signaling pathway. The soluble form, sIL-6R, binds to IL-6 with similar affinity, and then activates gp130. This binding activates the trans-signaling pathway of IL-6.
Reference: Rothaug M, Becker-Pauly C, Rose-John S. The role of interleukin-6 signaling in nervous tissue. Biochim Biophys Acta (2016) 1863:1218–27. doi:10.1016/j.bbamcr.2016.03.018
Gp130 is a glycoprotein, a common receptor and signal transducer subunit shared among all IL-6 family cytokines. Since membrane bound IL-6 can only be found on some cells, while as gp130 is ubiquitously expressed, the trans-signaling of IL-6 pathway allows IL-6 to modulate a broader variety of cells.
It is important to note that classic IL-6 signaling promotes the synthesis of acute-phase proteins in hepatocyte, which have anti-inflammatory properties, while as IL-6 trans-signaling is pro-inflammatory. It is not however, that IL-6 trans-signaling is detrimental to host health, as it plays important roles in inflammatory reactions, for example, IL-6 trans-signaling is critical to regulate the transition from neutrophil to monocyte and prevent excessive tissue damage. Suppression of IL-6 trans-signaling also does not protect tissues from damage in many diseases. Since IL-6 plays a fundamental part in many intertwining biological processes, IL-6 classic and trans-signaling pathways play distinct pathogenetic roles in different diseases.
First IL-6 binds to mbIL-6R, which then binds to two units of gp130. The resulting complex activates a variety of gp130 signaling pathways: the YxxQ motif of this complex activates JAK/STAT3 pathway; The Y759 motif activates SHP2/Gab/MAPK pathway, to name a few. The details of these pathways can be seen in the Boster pathway map. The main difference between mechanisms of the IL-6 classic and trans-signaling pathway is in the latter, IL-6 binds to sIL-6R in the body fluids and activates gp130. Since gp130 is universally expressed, this pathway can affect more cell types than its classic counterpart.
Membrane bound gp130 can also be cleaved into soluble form. Sgp130 is found in human plasma in high concentration, 100–400 ng/ml according to some studies. sgp130 reacts with IL-6/sIL-6R complex with the same affinity as membrane bound gp130, and acts as an inhibitor of IL-6 trans-signaling pathway. Since sgp130 does not affect IL-6 or mbIL-6R, it can be used as an experimental tool to specifically inhibit IL-6 trans-signaling pathway.
Reference: Scheller J, Grötzinger J, Rose-John S. Updating interleukin-6 classic- and trans-signaling. Signal Transduct (2006) 6:240–59. doi:10.1002/sita.200600086
Two distinct mechanisms generate sIL-6R in humans. First metalloproteases (ADAM family, most prominently ADAM10 and ADAM17) cleaves mbIL-6R from cell membranes. Second, cells translate a differentially spliced IL-6R mRNA lacking the transmembrane and cytosolic domains. Both mechanisms release the resulting sIL-6R into the body fluids. However metalloprotease activity is believed to regulate sIL-6R levels, instead of translation of differentially spliced IL-6R mRNA. In mouse, only metalloprotease cleavage of mbIL-6R can generate sIL-6R.
IL-6 contains 4 alphahelical chains arranged in a top-top-down-down topography. 3D details see this link: IL-6 interactive 3D structure
IL-6 receptor consists mostly of beta-strands forming a 3D details see this link: IL-6R interactive 3D structure
IL-6 is located on Chromosome 7 location NC_000007.14, position 22725889 to 22732002
A total of 10 members have been identified from the IL-6 family. They are IL-6, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotropin-1 (CT-1), cardiotrophin-like cytokine (CLC), neuropoietin (NP), IL-11, IL-27 (also known as IL-30), and IL-31. All family members share gp130 as a common receptor except IL-31. Though they share the some receptors, each family member when bound to its receptor forms different signal-transducing complex, leading to distinct downstream reactions.
Interleukin-6 (IL-6) was discovered in 1986 by Hirano T, et al, as a stimulating factor for B cell IgG production. Later it was found to be related to many biological processes including organ development, acute-phase responses, inflammation, and immune responses.
Reference: Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature (1986) 324:73–6. doi: 10.1038/324073a0; Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol (1998) 16:249–84. doi:10.3109/08830189809042997
Chondrocytes express IL-6 and can induce hepatocytic secretion of acute phase proteins, leading to acute-phase reaction.
Endothelial cells express IL-6 and can suppress inducible regulatory T cells development. With presence of TGF beta, IL-6 also promotes Th17 cell activities.
Osteoblasts express IL-6 but the effects are a mixture of anti and pro-inflammatory reactions.
Smooth muscle cells express IL-6 and help guide T cells migrate to inflammation sites.
Synoviocytes express IL-6 and promotes differentiation of CD8+ T cells into cytotoxic T cells.
T cells express IL-6 and mediates a wide variety of biological effects, depending on the environment.
Epithelial cells express IL-6 and with presence of IL-3, promotes the proliferation of hematopoietic stem cells.
Fibroblasts express IL-6 that promotes megakaryocyte maturation.
Monocytes/macrophages express IL-6 that promotes hematopoietic progenitor cell growth and differentiation.