Regulation of IL-6-type cytokine responses by MAPKs

IL-6 (interleukin 6)-type cytokines are pleiotropic molecules, critical for cellular homoeostasis and with well-recognized roles in several human diseases. They all activate JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling and, depending on the particular cytokine, cell type and cellular environment, they can also trigger the activation of MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) cascades. Although it is clear that JAK/STAT and MAPK reciprocally regulate each other, how these signalling pathways are fully integrated remains to be fully understood. Not only do cells have to be able to integrate and conciliate what are often contradictory signalling cues, but they are also subject to complex regulatory mechanisms involving these pathways. More specifically, we have shown recently that ERK2 (extracellular-signal-regulated kinase 2) is required for the transcriptional regulation of gp130 (glycoprotein 130), a key receptor complex component for most IL-6-type cytokines. ERK2 not only binds to the gp130 promoter and is required for full expression of the protein, but it also regulates the stability of gp130 mRNA. This function of ERK2 is not shared by ERK1 and it probably represents an entirely novel function for this prominent kinase.