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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).

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^[1]. Cytoplasmic parts of cytokine receptors interact with JAK kinases, which happen to pass the signal to STAT3 via phosphorylation^[2] Apart from JAK-STAT pathway there may be also other pathways involved such as RAS and MAPK.

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^[3].
Studies from double knock-out gp130-/- mice embryos show impaired myocardial and hematopoiesis development^[4].
IL-6R expression is in contrast to gp130 restricted to just certain cell types^[5]. 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^[6]. The affinity of membrane bound and soluble IL-6R to IL-6 are similar^[7]. 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^[8]. 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^[9].

Trans-signaling via IL-6 could be a crucial transition mechanism between acute and chronic stage of the disease. Examples include inflammatory bowel disease^[10], peritonitis^[11] and rheumatoid arthritis^[12].