IL-6 Family Signaling Pathway

The IL-6 family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1.

All cytokines in the IL-6 family signal via the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway. Also, other interleukin members such as IL-2, IL-10, IL-12 family, can actiate Jak/STAT signaling pathway.

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IL-6 Family Signaling Pathway

IL-6 Family Signaling Pathway Overview

Besides their functions in inflammation and the immune response, these so-called IL-6 family cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility.

The first event in activation of the Jak STAT signalling pathway is the ligand-induced homo- or hetero-dimerization of signal-transducing receptor subunits. All IL-6 family cytokines recruit gp130 to their receptor complexes. They either signal via gp130 alone or in combination with LIFR or the recently cloned OSMR, which are all able to activate Jaks and to recruit STAT proteins. IL-6 induces gp130-homodimerization, whereas CNTF, LIF, and CT-1 signal via heterodimerization of gp130 and LIFR.

OSM was first described to signal via gp130–LIFR heterodimers, but at least in mice the physiological signalling receptor consists of gp130 and OSMR. For IL-11 it is not clear whether, similarly to IL-6, it induces gp130 homodimer formation or, alternatively, recruits an additional, as-yet-unidentified, receptor subunit.

IL-6 leads to the activation of Jak1, Jak2 and Tyk2. This holds true also for the other IL-6-type cytokines IL-11, LIF, OSM, CT-1 and CNTF. Which kinases are involved and to what extent a certain kinase is activated varies among cells and possibly reflects different expression levels of Jaks.

In 1994 it was discovered that IL-6 family cytokines utilize tyrosine kinases of the Jak family and transcription factors of the STAT family as major mediators of signal transduction, a feature they share with the IFNs and many other cytokines and growth factors.

Gp130-associated kinases Jak1, Jak2, and Tyk2 become activated upon stimulation, and the cytoplasmic tail of gp130 is phosphorylated. Several phosphotyrosine residues of gp130 are docking sites for STAT factors with matching SH2 domains, mainly STAT3 and STAT1. Subsequently, STATs also become phosphorylated, form dimers and translocate to the nucleus, where they regulate transcription of target genes.

References

1. Heinrich, P. C., Behrmann, I., Serge, H., Hermanns, H. M., Müller-Newen, G., & Schaper, F. (2003). Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochemical journal, 374(1), 1-20.
2. Heinrich, P. C., Behrmann, I., Müller-Newen, G., Schaper, F., & Graeve, L. (1998). Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochemical journal, 334(2), 297-314.