title: Receptor interacting protein-2 plays a critical role in human lung epithelial cells survival in response to Fas-induced cell-death.
abstract: Lung epithelial cell death is critical to the lung injury that occurs in the acute respiratory distress syndrome. It is known that FasL plays a prominent role in this lung cell death pathway and may work in part through activation of the receptor interacting protein-2 (RIP2). RIP2 is serine/threonine kinase with a C-terminal caspase activation and recruitment domain (CARD). This CARD contains a highly conserved, predicted tyrosine phosphorylation site. Thus, involvement of tyrosine phosphorylation in the CARD domain of RIP2 may play a critical role in Fas-mediated apoptosis in the human lung immune system. To test this hypothesis, human lung epithelial cells (BEAS-2B) were induced to undergo cell death in response to the Fas agonist antibody CH11 with and without manipulation of endogenous RIP2 concentrations. We show that CH11 increases lung epithelial cell death in a dose-dependent manner as determined by LDH release and nuclear condensation. Fas-induced LDH release was inhibited by RIP2 knock-down. Reduced levels of RIP2 in BEAS-2B cells after treatment with RIP2 siRNA were confirmed by immunoblot. Overexpression of RIP2 in BEAS-2B cells synergized with Fas ligand-induced LDH release in a dose-dependent manner. Finally, mutation of the tyrosine phosphorylation site in CARD of RIP2 protected BEAS-2B cells from Fas ligand induced cell death. Thus RIP2's CARD tyrosine phosphorylation may represent a new therapeutic target to promote the survival of human lung epithelial cells in disorders that lead to acute lung injury and ARDS.
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mohd Akhlakur
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kruthika
authors.initials: K
authors.lastname: Sundaram
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Srabani
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Gavrilin
authors.affiliation: Dorothy M. Davis Heart and Lung Research Institute, Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism*; D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D053222:Fas Ligand Protein / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D045022:Lactate Dehydrogenases / Q000096:biosynthesis; D009154:Mutation; D010766:Phosphorylation; D055550:Protein Stability; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D019014:fas Receptor; D045022:Lactate Dehydrogenases; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2