transsignaling

Transsignaling is a mode of intercellular communication in which a cytokine signals to cells that lack the corresponding membrane receptor by using a soluble form of that receptor. This mechanism expands the range of cells able to respond to a given signal and can influence the magnitude, duration, and tissue distribution of responses in immune and inflammatory contexts.

Mechanism and scope:

In the best-described example, interleukin-6 (IL-6) binds to a soluble IL-6 receptor (sIL-6R). The IL-6/sIL-6R complex then engages gp130 on the surface of target cells, triggering intracellular signaling pathways such as JAK/STAT, MAPK, and PI3K/AKT. Because gp130 is widely expressed, many cell types can respond to IL-6 through trans-signaling, including those that do not express membrane-bound IL-6R. Transsignaling is not limited to IL-6; other cytokines are thought to use similar mechanisms, though the specifics vary by ligand and receptor biology.

Physiological and pathological relevance:

Trans-signaling contributes to the amplification and spread of inflammatory signals, and is implicated in various inflammatory and autoimmune conditions. It can influence tissue repair, vascular permeability, and immune cell recruitment. The relative balance between classic (receptor-bound) and trans-signaling is context-dependent and can shape disease outcomes.

Therapeutic implications:

Because trans-signaling can be pro-inflammatory while preserving some beneficial classic signaling, selectively inhibiting trans-signaling is a focus of research. Examples include strategies that sequester cytokine–soluble receptor complexes (such as soluble gp130-based approaches) to block IL-6 trans-signaling, with the aim of reducing chronic inflammation while maintaining normal immune defense.