The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition

Interleukin-6 has long been recognized as a prototypic pro-inflammatory cytokine that is involved in the pathogenesis of all inflammatory diseases. Activation of the gp130 homodimer by IL-6 leads to the initiation of Jak/STAT signaling, a pathway that is often constitutively switched on in inflammatory malignancies. However, a plethora of studies in the last decade has convincingly shown that only signaling via the soluble IL-6R (trans-signaling) accounts for the deleterious effects of IL-6, whereas classic signaling via the membrane-bound receptor is essential for the regenerative and anti-bacterial effects of IL-6 (classic signaling). In this review, we highlight recent developments in the field of IL-6 research, and specifically focus on advances towards a safe and specific inhibition of IL-6 trans-signaling.