Interleukin-6 (IL-6) is a cytokine with multiple functions, including regulation of the immune and nervous systems, liver regeneration, and metabolic control. IL-6 binds to the 80 kDa IL-6 receptor (IL-6R) on target cells, forming a complex with gp130, which initiates intracellular signaling via the JAK/STAT pathway. However, a soluble form of IL-6R (sIL-6R) can also bind IL-6, allowing trans-signaling to occur in cells that lack the membrane-bound IL-6R. This process, known as trans-signaling, is pro-inflammatory and involves the activation of gp130, leading to the production of inflammatory cytokines and chemokines. In contrast, classic IL-6 signaling via the membrane-bound IL-6R is involved in regenerative and anti-inflammatory activities, such as epithelial cell regeneration and inhibition of apoptosis. The availability of sIL-6R and sgp130, a soluble form of gp130, acts as a buffer in the blood, preventing systemic effects of IL-6 under steady-state conditions. Specific blockade of IL-6 trans-signaling using sgp130Fc has shown therapeutic potential in various inflammatory diseases, including atherosclerosis and Castleman's disease. The understanding of IL-6 biology has significant implications for the development of targeted therapies aimed at modulating IL-6 signaling.Interleukin-6 (IL-6) is a cytokine with multiple functions, including regulation of the immune and nervous systems, liver regeneration, and metabolic control. IL-6 binds to the 80 kDa IL-6 receptor (IL-6R) on target cells, forming a complex with gp130, which initiates intracellular signaling via the JAK/STAT pathway. However, a soluble form of IL-6R (sIL-6R) can also bind IL-6, allowing trans-signaling to occur in cells that lack the membrane-bound IL-6R. This process, known as trans-signaling, is pro-inflammatory and involves the activation of gp130, leading to the production of inflammatory cytokines and chemokines. In contrast, classic IL-6 signaling via the membrane-bound IL-6R is involved in regenerative and anti-inflammatory activities, such as epithelial cell regeneration and inhibition of apoptosis. The availability of sIL-6R and sgp130, a soluble form of gp130, acts as a buffer in the blood, preventing systemic effects of IL-6 under steady-state conditions. Specific blockade of IL-6 trans-signaling using sgp130Fc has shown therapeutic potential in various inflammatory diseases, including atherosclerosis and Castleman's disease. The understanding of IL-6 biology has significant implications for the development of targeted therapies aimed at modulating IL-6 signaling.