Toll-Like Receptor-Mediated Production of IL-1Ra Is Negatively Regulated by GSK3 via the MAPK ERK1/2

IL-1 receptor antagonist (IL-1Ra), a natural inhibitor of IL-1 beta, has been shown to regulate the progression of a variety of inflammatory diseases. Although experimental studies and clinical trials have demonstrated the importance of IL-1Ra in chronic inflammatory diseases, the cellular mechanisms responsible for regulating the endogenous production of IL-1Ra by innate immune cells are currently unresolved. In the present study, we identify that glycogen-synthase kinase 3 (GSK3) regulates the production of the anti-inflammatory cytokine IL-1Ra via its ability to regulate the MAPK ERK1/2 in TLR-stimulated cells. Elucidation of the cell-signaling pathway by which GSK3 controlled ERK activity demonstrated that GSK3 inhibition resulted in an abrogation in the levels of the inhibitory residue serine 71 on Rac1 and increased the ability of Rac1 to interact with and activate p21-activated protein kinase. siRNA-mediated knockdown of Rac1 attenuated the ability of GSK3 inhibition to augment phopsho-ERK1/2 levels in LPS-stimulated immune cells. Moreover, inhibiting the ability of GSK3 to augment ERK1/2 activity abrogated enhanced IL-1Ra production by GSK3-inhibited cells. Our findings identify that GSK3 negatively regulates the levels of IL-1Ra produced by LPS-stimulated innate immune cells. The Journal of Immunology, 2009, 182: 547-553.