A model for cytokine-mediated up-regulation of the β -cell Reg genes leading to β -cell regeneration. Interleukin-22 (red) binds to its receptor complex, IL-22Rα/IL-10Rβ, which activates the Stat3 transcription factor protein (1), STAT3 then migrates into the nucleus of the β-cell and stimulates Reg gene transcription and translation (green). Secreted Reg proteins are then thought to activate Cyclin D1. This allows the β-cell to enter the G1/S transition of the cell cycle leading to regeneration. IL-22 can also activate the MAP3 kinases leading to Cyclin D1 (2), which in turn inactivates the Retinoblastoma (Rb). Platelet-derived growth factor (PDGF) (blue) similarly leads the activation of Cyclin D1, which in turn inactivates Rb allowing the release of sequestered transcription factors (TF) essential for the G1–S progression of the cell cycle. Reg2 gene expression by activating Stat3, believed to be caused by receptor-induced Src kinase activity. The known signaling pathways (black and blue) and the proposed signaling pathways (green) are identified.