Published ahead of print on November 21, 2008, doi:10.1164/rccm.200712-1787OC
© 2009 American Thoracic Society doi: 10.1164/rccm.200712-1787OC
Post-Transcriptional Regulation of Urokinase-type Plasminogen Activator Receptor Expression in Lipopolysaccharide-induced Acute Lung Injury1 The Texas Lung Injury Institute, University of Texas Health Science Center, Tyler, Texas; 2 Department of Pathology and Laboratory Medicine, the University of Pennsylvania, Philadelphia, Pennsylvania; and 3 Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama Correspondence and requests for reprints should be addressed to Sreerama Shetty, Ph.D., Professor of Medicine, The Texas Lung Injury Institute, The University of Texas Health Center at Tyler, 11937 U.S. Hwy. 271, Lab C-6, Tyler, TX 75708. E-mail: sreerama.shetty{at}uthct.edu Rationale: Urokinase-type plasminogen activator (uPA) receptor (uPAR) is required for the recruitment of neutrophils in response to infection. uPA induces its own expression in lung epithelial cells, which involves its interaction with cell surface uPAR. Regulation of uPAR expression is therefore crucial for uPA-mediated signaling in infectious acute lung injury (ALI). Objectives: To determine the role of uPA in uPAR expression during ALI caused by sepsis. Methods: We used Western blot, Northern blot, Northwestern assay, and immunohistochemistry. Phosphate-buffered saline– and lipopolysaccharide (LPS)-treated wild-type and uPA–/– mice were used. Measurements and Main Results: Biological activities of uPA, including proteolysis, cell adhesion, migration, proliferation, and differentiation, are dependent on its association with uPAR. Bacterial endotoxin (LPS) is a major cause of pulmonary dysfunction and infection-associated mortality. The present study shows that LPS induces uPAR expression both in vitro and in vivo, and that the mechanism involves post-transcriptional stabilization of uPAR mRNA by reciprocal interaction of phosphoglycerate kinase (PGK) and heterogeneous nuclear ribonucleoprotein C (hnRNPC) with uPAR mRNA coding region and 3' untranslated region determinants, respectively. The process involves tyrosine phosphorylation of PGK and hnRNPC. uPA–/– mice failed to induce uPAR expression after LPS treatment. In these mice, LPS treatment failed to alter the binding of PGK and hnRNPC protein with uPAR mRNA due to lack of tyrosine phosphorylation. Conclusions: Our study shows that induction of LPS-mediated uPAR expression is mediated through tyrosine phosphorylation of PGK and hnRNPC. This involves expression of uPA as an obligate intermediary.
Key Words: LPS • urokinase-type plasminogen activator • urokinase-type plasminogen activator receptor • tyrosine phosphorylation
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