Focal adhesion kinase-mediated activation of glycogen synthase kinase 3? regulates IL-33 receptor internalization and IL-33 signaling.

ABSTRACT: IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. Long form ST2 (ST2L), the receptor for IL-33, is expressed on immune effector cells and lung epithelia and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system; however, its upstream internalization has not been studied. In this study, we demonstrate that glycogen synthase kinase 3? (GSK3?) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3?. GSK3? was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3? binding site mutant (ST2L(S446A)) and phosphorylation site mutant (ST2L(S442A)) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3? activation and ST2L internalization. Furthermore, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3? might serve as a unique strategy to lessen pulmonary inflammation.

SUBMITTER: Zhao J 

PROVIDER: S-EPMC4363995 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature