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

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          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 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β 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 GSK3β 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/GSK3β might serve as a unique strategy to lessen pulmonary inflammation.

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          Author and article information

          Journal
          J. Immunol.
          Journal of immunology (Baltimore, Md. : 1950)
          1550-6606
          0022-1767
          Jan 15 2015
          : 194
          : 2
          Affiliations
          [1 ] Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
          [2 ] Department of Medicine, Acute Lung Injury Center of Excellence, Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 zhaoy3@upmc.edu.
          Article
          jimmunol.1401414 NIHMS641505
          10.4049/jimmunol.1401414
          4363995
          25472995
          5bd74310-add4-430c-b15a-ad1166b5c663
          Copyright © 2015 by The American Association of Immunologists, Inc.
          History

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