Interleukin-6 family signaling

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Homo sapiens
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The interleukin-6 (IL6) family of cytokines includes IL6, IL11, IL27, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin 1 and 2 (CT-1) and cardiotrophin-like cytokine (CLC) (Heinrich et al. 2003, Pflanz et al. 2002). The latest addition to this family is IL31, discovered in 2004 (Dillon et al. 2004). The family is defined largely by the shared use of the common signal transducing receptor Interleukin-6 receptor subunit beta (IL6ST, gp130). The IL31 receptor uniquely does not include this subunit, instead it uses the related IL31RA. The members of the IL6 family share very low sequence homology but are structurally highly related, forming anti-parallel four-helix bundles with a characteristic “up-up-down-down” topology (Rozwarski et al. 1994, Cornelissen et al. 2012).

Although each member of the IL6 family signals through a distinct receptor complex, their underlying signaling mechanisms are similar. Assembly of the receptor complex is followed by activation of receptor-associated Janus kinases (JAKs), believed to be constitutively associated with the receptor subunits.Activation of JAKs initiates downstream cytoplasmic signaling cascades that involve recruitment and phosphorylation of transcription factors of the Signal transducer and activator of transcription (STAT) family, which dimerize and translocate to the nucleus where they bind enhancer elements of target genes leading to transcriptional activation (Nakashima & Taga 1998).

Negative regulators of IL6 signaling include Suppressor of cytokine signals (SOCS) family members and PTPN11 (SHP-2).

IL6 is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep.

IL6 and IL11 bind their corresponding specific receptors IL6R and IL11R respectively, resulting in dimeric complexes that subsequently associate with IL6ST, leading to IL6ST homodimer formation (in a hexameric or higher order complex) and signal initiation. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL6 activities

LIF, CNTF, OSM, CTF1, CRLF1 and CLCF1 signal via IL6ST:LIFR heterodimeric receptor complexes (Taga & Kishimoto 1997, Mousa & Bakhiet 2013). OSM signals via a receptor complex consisting of IL6ST and OSMR. These cytokines play important roles in the regulation of complex cellular processes such as gene activation, proliferation and differentiation (Heinrich et al. 1998).

Antibodies have been developed to inhibit IL6 activity for the treatment of inflammatory diseases (Kopf et al. 2010).
Literature References
PubMed ID Title Journal Year
22595692 Plasticity and cross-talk of interleukin 6-type cytokines

Schaper, F, Garbers, C, Grötzinger, J, Müller-Newen, G, Scheller, J, Hermanns, HM, Rose-John, S

Cytokine Growth Factor Rev. 2012
26551279 Modular organization of Interleukin-6 and Interleukin-11 α-receptors

Garbers, C, Lokau, J, Aparicio-Siegmund, S, Nitz, R, Scheller, J

Biochimie 2015
20410258 IL-6: from its discovery to clinical applications

Kishimoto, T

Int Immunol 2010
7632928 Interleukin-6 family of cytokines and gp130

Kishimoto, T, Narazaki, M, Akira, S, Taga, T

Blood 1995
9143707 Gp130 and the interleukin-6 family of cytokines

Kishimoto, T, Taga, T

Annu. Rev. Immunol. 1997
9685167 gp130 and the IL-6 family of cytokines: signaling mechanisms and thrombopoietic activities

Nakashima, K, Taga, T

Semin. Hematol. 1998
9716487 Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway

Heinrich, PC, Schaper, F, Behrmann, I, Müller-Newen, G, Graeve, L

Biochem. J. 1998
8666978 Gp130, a shared signal transducing receptor component for hematopoietic and neuropoietic cytokines

Taga, T

J. Neurochem. 1996
12773095 Principles of interleukin (IL)-6-type cytokine signalling and its regulation

Schaper, F, Heinrich, PC, Behrmann, I, Haan, S, Hermanns, HM, Müller-Newen, G

Biochem J 2003
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