J. Clin. Invest. 108: 1729–1733 (2001). DOI: 10.1172/JCI200114660. to CT-1-specific receptor (CT-1Rα)(Figure 1). As might be expected, gp130-neutralizing antibodies can inhibit the biological activities of all IL-6 family cytokines (1, 3). gp130 signals are mediated by tyrosine kinases of the JAK family and by their binding partners, transcription factors of the STAT family (reviewed in ref. 6). The general first event in activation of the JAK/STAT signaling pathway is the ligand-induced homo-or heterodimerization of signal-transducing receptor subunits—gp130 in the case of these receptors. Thereafter, JAKs (JAK1, JAK2, and Tyk2) are activated and in turn phosphorylate gp130 at several residues, providing docking sites for SH2 domain-containing molecules, such as STAT1 or STAT3 members of the STAT family. Upon phosphorylation, the STATs translocate as dimers into the nucleus, where they bind to promoter regions of their specific response genes. Altered forms of gp130 that fail to induce activation of JAKs fail to transduce an IL-6 proliferative signal. gp130 is also linked to the Ras/Raf/mitogen-activated protein kinase (Ras/Raf/MAPK) pathway via the adapter molecule SHP-2, which becomes recruited to one particular phosphotyrosine residue in the stimulated gp130 and undergoes tyrosine phosphorylation by JAKs. These cascades may activate the nuclear factor NF-IL-6, a leucine zipper-containing transcription factor homologous to C/EBP. NF-IL-6 mediates not only the expression of inflammatory cytokines, but also the expression of IL-6–inducible genes, such as acute-phase proteins in hepatocytes (3).

Activation of STATs is transient, and several mechanisms for STAT inactivation exist. First, a protein named PIAS3 blocks DNA binding of activated STAT3, as well as STAT3-mediated gene activation (6). It forms part of a group of gp130 signaling inhibitors known as protein