gp130 cytokine signaling in the pituitary gland: a paradigm for cytokine-neuro-endocrine pathways.

Unlike most other classes of receptors, where the cytoplasmic domain is necessary for signal transduction, receptors for IL-6 and other related cytokines signal solely by virtue of their ability to form a larger receptor complex with a common subunit, the transmembrane glycoprotein gp130 (1). For instance, binding of IL-6 to IL-6Rα, the α subunit of the functional receptor, triggers the association of IL-6Rα with gp130 (1, 2). Indeed, even a soluble form of IL-6Rα, entirely lacking the intracellular region of the protein, can bind to its ligand and to surface-expressed gp130, producing a normal IL-6 signal (1). The ligands of these various receptors are therefore referred to as the gp130 cytokine receptor family. As summarized in Figure 1, gp130 functions as a common cytokine signal transducer for IL-6, leukemia inhibitory factor (LIF), IL-11, oncostatin M (OSM), ciliary neurotrophic factor (CNTF), and cardiotropin-1 (CT-1), all of which bind specific receptors (their α subunits) but use the gp130 protein as the initial cellular signal transducer (2, 3). Because of this broad physiological role, the term gp130 is commonly used, in addition to its official human genome organization (HUGO) designation as the IL-6 signal transducer, or IL6ST. The human gp130 consists of an extracellular domain of 597 amino acids, with a single transmembrane domain of 22 amino acids, and a cytoplasmic domain of 277 amino acids. As with other hemopoietic cytokine receptors, gp130 contains a cytokine receptor homology region that includes fibronectin type III domains as well as four positionally conserved cysteine residues and a WSXWS motif (1, 3) (Figure 1). While the expression of the gp130 cDNA alone does not confer the binding of IL-6 or the other family cytokines, gp130 and IL-6Ra together form a high-affinity IL-6 binding site. In the mouse, gp130 is ubiquitously expressed in adult organs, as well as in embryonic stem cells and in embryos as early as day 6 of gestation (3). Expression of gp130 therefore does not parallel that of the α subunit of any of the receptors of the cytokine family, nor of any specific cytokine of the IL-6 family. These factors show some functional redundancy in the immune, hematopoietic, nervous, and neuro-endocrine systems. For example, macrophage differentiation, expression of acute-phase proteins by hepatocytes, and neuronal survival and differentiation can all be induced by multiple gp130 cytokines. Conversely, as is extensively reviewed in refs. 3–5, these cytokines also exhibit specific biological activities. Considering that gp130 is ubiquitously expressed, the time and place at which gp130 functions in vivo appears to be determined by spatially and temporally regulated expression of specific cytokine-binding receptor chains or of the cytokines themselves. In addition, soluble gp130, probably translated from an alternative spliced mRNA, can neutralize receptor signaling complexes, thereby acting as an antagonist (6). Below, I discuss the regulation of cytokine and cytokine receptor function in the pituitary gland and its importance for neuro-endocrine–stress responses.