Figure 1. IL-6 mediates a series of cell signaling pathways. IL-6 binds to the membrane IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). The binding of IL-6 to both receptors results in the dimerization and activation of the glycosylated type I membrane protein of 130–150 kDa (gp130). The dimerization of signaling receptor gp130 mediates the activation of Janus kinases (JAKs) and subsequent activation of phosphatase Src homology domains containing tyrosine phosphatase-2 (SHP-2), the ras/raf/mitogen-activated protein kinase (MAPK) pathway, signal transducer and activator of transcription factor-3 (STAT-3), and PI3K/Akt, which are translocated into the nucleus to activate target genes. IL-6/mIL-6R medicated activation of gp130 induces IL-6 classic signaling pathway, leading to anti-inflammatory biological activities; while IL-6/sIL-6R induced the activation of gp130 leads to activation of IL-6 trans-signaling pathway that results in pro-inflammatory responses.