Figure 3.

Model of canonical IL-6 signaling versus IL-6 trans-signaling in tumor progression and metastases. In the canonical IL-6 signaling pathway, the IL-6 receptor subunit is membrane bound and forms a heterotrimer with two gp130 subunits. When IL-6 binds to the receptor, STAT3 is activated in a JAK-dependent manner that leads to increased RANKL expression. IL-6 may also activate AKT via increased JAK-dependent PI3K activity and result in cell survival and anti-apoptosis signaling. Concomitantly, increased MAPK activity downstream of JAK activation can lead to upregulated cell growth, proliferation, and mitosis. In the IL-6 trans-signaling pathway, IL-6 first binds to the truncated sIL6R. The IL-6/sIL6R complex then binds to the membrane-bound gp130 dimer to form an IL-6 trans-signaling complex. Due to the fact that the sIL-6R lacks a membrane signaling domain, there appears to be significant differences in the intracellular signaling pathways. While IL-6 trans-signaling also leads to phosphorylation and activation of STAT3, increased cell survival, proliferation, and mitosis occurs in an AKT-and MAPK-independent manner. The exact mechanisms for IL-6 trans-signaling leading to increased cell survival, proliferation, and mitosis are not yet known.

Abbreviations: IL-6, interleukin 6; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; RANKL, receptor activator of nuclear factor κB ligand; sIL6R, soluble IL-6 receptor; STAT3, signal transducer and activator of transcription 3.