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=Trans-signaling=

Trans-signaling is a process in which a soluble receptor binds to a signaling component in order to induce a productive response. This means that the receptor is non-functional without the signaling component which serves hence as a regulatory element in signal transduction. The signaling component is called gp130 (CD130) and is common for several soluble receptors. These soluble receptors involved in trans-signaling are of IL-6 cytokine family, which include IL-6, IL-11, leukemia inhibitory factor (LIF), oncostatin M, ciliary neutrophic factor (CNTF) and cardiotrophin-1 (CT-1).

Signal transduction
The initiation of a signaling process is dimerization through ligands of cytokine receptors components. Receptor cytoplasmic parts then serve as substrate for further downstream signaling. Cytoplasmic parts of cytokine receptors interact with JAK kinases, which happen to pass the signal to STAT3 via phosphorylation Apart from JAK-STAT pathway there may be also other pathways involved such as RAS and MAPK.

Mechanism of IL-6 trans-signaling
Glycoprotein 130 is a transmembrane protein which is ubiquitously expressed in almost all organs including heart, kidney, spleen, liver, lung, placenta, and brain. Even cells that do not express receptors for IL-6 or IL- 6-related cytokines express gp130.

Studies from double knock-out gp130-/- mice embryos show impaired myocardial and hematopoiesis development.

IL-6R expression is in contrast to gp130 restricted to just certain cell types. In comparison with other cytokines IL-6 is naturally expressed as a soluble sIL-6R. SIL-6 could be generated either by differential mRNA splicing or by proteolytic cleavage of already anchored protein. The affinity of membrane bound and soluble IL-6R to IL-6 are similar. SIL-6R makes a complex with IL-6 that can afterwards activate cells by gp130. This mechanism enables activation of cells, which lack membrane-bound IL-6R. In some manner it resembles autocrine or paracrine signaling of gp130 associated receptors. This mode of action quite nicely explains redundancy of IL-6 signaling, activation of other cytokine receptors such as LIFR, IL-11R or CNTF could be easily replaced by IL-6 trans-signaling.

The self-sustaining regulatory loop of IL-6 trans-signaling could be demonstrated on smooth muscle cells. This type of cells usually does not express much of membrane-bound IL-6R, therefore it takes advantage of sIL-6R/IL-6 complex, which serve as autocrine signal for up-regulation of gp130 accompanied with IL-6 secretion. As a result the cells undergoes proliferation and is driven into a proinflammatory state.

Clinical significance
Trans-signaling via IL-6 could be a crucial transition mechanism between acute and chronic stage of the disease. Examples include inflammatory bowel disease, peritonitis and rheumatoid arthritis.