Interleukin-6 signaling axis (IL-6 axis)

The Interleukin-6 (IL-6) signaling axis is a fundamental pathway regulating immune responses, inflammation, and hematopoiesis [1, 6]. It involves the pleiotropic cytokine IL-6 binding to its specific receptor (IL-6R), which then associates with the signal-transducing subunit gp130 to initiate intracellular signaling via the JAK/STAT, MAPK, and PI3K/Akt pathways [2, 7]. The axis operates through 'classic signaling' via membrane-bound receptors, primarily mediating anti-inflammatory and regenerative effects, and 'trans-signaling' via soluble receptors, which drives pro-inflammatory responses in a wider range of cells [10]. Dysregulation of this axis is a key driver in autoimmune diseases like rheumatoid arthritis, systemic inflammatory conditions such as cytokine release syndrome, and various malignancies [3, 8]. Therapeutic intervention is achieved through monoclonal antibodies that neutralize the IL-6 ligand (e.g., siltuximab) or block the IL-6 receptor (e.g., tocilizumab), as well as small-molecule inhibitors of downstream Janus kinases [4, 13]. Monitoring efficacy often involves measuring C-reactive protein (CRP) levels, which are directly regulated by IL-6 signaling in the liver [3, 11]. While highly effective, targeting this axis carries risks such as increased susceptibility to serious infections and gastrointestinal perforations [15].

Other names

IL-6 pathwayIL-6/STAT3 pathwayIL-6/gp130 signalingIL-6/IL-6R axisInterleukin-6/Interleukin-6 receptor signaling axisIL-6 / IL-6 signaling axis

The axis is targeted through three primary mechanisms: neutralization of the IL-6 ligand by monoclonal antibodies, antagonism of the IL-6 receptor (blocking both membrane-bound and soluble forms), and inhibition of downstream Janus kinases (JAKs) to prevent intracellular signal transduction [3, 13, 15].