title: Tumor suppressor death-associated protein kinase attenuates inflammatory responses in the lung.
abstract: Death-associated protein kinase (DAPk) is a tumor suppressor thought to inhibit cancer by promoting apoptosis and autophagy. Because cancer progression is linked to inflammation, we investigated the in vivo functions of DAPk in lung responses to various acute and chronic inflammatory stimuli. Lungs of DAPk knockout (KO) mice secreted higher concentrations of IL-6 and keratinocyte chemoattractant (or chemokine [C-X-C motif] ligand 1) in response to transient intranasal administrations of the Toll-like receptor-4 (TLR4) agonist LPS. In addition, DAPk-null macrophages and neutrophils were hyperresponsive to ex vivo stimulation with LPS. DAPk-null neutrophils were also hyperresponsive to activation via Fc receptor and Toll-like receptor-3, indicating that the suppressive functions of this kinase are not restricted to TLR4 pathways. Even after the reconstitution of DAPk-null lungs with DAPk-expressing leukocytes by transplanting wild-type (WT) bone marrow into lethally irradiated DAPk KO mice, the chimeric mice remained hypersensitive to both acute and chronic LPS challenges, as well as to tobacco smoke exposure. DAPk-null lungs reconstituted with WT leukocytes exhibited elevated neutrophil content and augmented cytokine secretion in the bronchoalveolar space, as well as enhanced epithelial cell injury in response to both acute and chronic inflammatory conditions. These results suggest that DAPk attenuates a variety of inflammatory responses, both in lung leukocytes and in lung epithelial cells. The DAPk-mediated suppression of lung inflammation and airway injury may contribute to the tumor-suppressor functions of this kinase in epithelial carcinogenesis.
authors: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Sigal
authors: S
authors: Nakav
authors: Shmuel
authors: S
authors: Cohen
authors: Sara W
authors: SW
authors: Feigelson
authors: Shani
authors: S
authors: Bialik
authors: David
authors: D
authors: Shoseyov
authors: Adi
authors: A
authors: Kimchi
authors: Ronen
authors: R
authors: Alon
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000378:metabolism; D064550:Death-Associated Protein Kinases; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000201:enzymology* / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D011961:Receptors, Fc / Q000378:metabolism; D013997:Time Factors; D014028:Tobacco Smoke Pollution; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology; D018183:Transplantation Chimera
chemical_list: D051017:Apoptosis Regulatory Proteins; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011961:Receptors, Fc; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D014028:Tobacco Smoke Pollution; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases