Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 843K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ernst, M. Articles by Dunn, A. R. Search for Related Content PubMed PubMed Citation Articles by Ernst, M. Articles by Dunn, A. R. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Social Bookmarking                      What's this?

Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response

Matthias Ernst¹, Melissa Inglese¹, Glen M. Scholz¹, Kenneth W. Harder¹, Fiona J. Clay¹, Steven Bozinovski³, Paul Waring⁴, Rima Darwiche², Tom Kay², Peter Sly⁵, Rachel Collins⁵, Debra Turner⁵, Margaret L. Hibbs¹, Gary P. Anderson³ and Ashley R. Dunn¹

¹ Ludwig Institute for Cancer Research, Royal Melbourne Hospital
² The Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital
³ Departments of Medicine and Pharmacology, University of Melbourne, Victoria 3050, Australia
⁴ Department of Pathology, Peter MacCallum Cancer Institute, East Melbourne, Victoria 3002, Australia
⁵ Centre for Child Health Research, University of Western Australia, Perth, WA 6872, Australia

Address correspondence to M. Ernst, Ludwig Institute for Cancer Research, PO Royal Melbourne Hospital, Victoria 3050, Australia. Phone: 61-3-3941-3149; Fax: 61-3-9341-3191. E-mail: matthias.ernst{at}ludwig.edu.au

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck^F/F "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y₄₉₉-residue in the Hck protein. Unlike their Hck^-/- "loss-of-function" counterparts, Hck^F/F "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck^F/F mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck^F/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF). Similarly, Hck^F/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck^F/F mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNF production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck^F/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.

Key Words: knock-in mutation • LPS • endotoxemia • macrophage • neutrophil

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Yanagisawa, S., Sugiura, H., Yokoyama, T., Yamagata, T., Ichikawa, T., Akamatsu, K., Koarai, A., Hirano, T., Nakanishi, M., Matsunaga, K., Minakata, Y., Ichinose, M. (2009). The Possible Role of Hematopoietic Cell Kinase in the Pathophysiology of COPD. Chest 135: 94-101 [Abstract] [Full Text]  
• Hong, H., Kitaura, J., Xiao, W., Horejsi, V., Ra, C., Lowell, C. A., Kawakami, Y., Kawakami, T. (2007). The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn. Blood 110: 2511-2519 [Abstract] [Full Text]  
• Ardizzone, T. D., Zhan, X., Ander, B. P., Sharp, F. R. (2007). Src Kinase Inhibition Improves Acute Outcomes After Experimental Intracerebral Hemorrhage. Stroke 38: 1621-1625 [Abstract] [Full Text]  
• Fumagalli, L., Zhang, H., Baruzzi, A., Lowell, C. A., Berton, G. (2007). The Src Family Kinases Hck and Fgr Regulate Neutrophil Responses to N-Formyl-Methionyl-Leucyl-Phenylalanine. J. Immunol. 178: 3874-3885 [Abstract] [Full Text]  
• Lieser, S. A., Shaffer, J., Adams, J. A. (2006). Src Tail Phosphorylation Is Limited by Structural Changes in the Regulatory Tyrosine Kinase Csk. J. Biol. Chem. 281: 38004-38012 [Abstract] [Full Text]  
• Okutani, D., Lodyga, M., Han, B., Liu, M. (2006). Src protein tyrosine kinase family and acute inflammatory responses. Am. J. Physiol. Lung Cell. Mol. Physiol. 291: L129-L141 [Abstract] [Full Text]  
• Giagulli, C., Ottoboni, L., Caveggion, E., Rossi, B., Lowell, C., Constantin, G., Laudanna, C., Berton, G. (2006). The Src Family Kinases Hck and Fgr Are Dispensable for Inside-Out, Chemoattractant-Induced Signaling Regulating beta2 Integrin Affinity and Valency in Neutrophils, but Are Required for beta2 Integrin-Mediated Outside-In Signaling Involved in Sustained Adhesion. J. Immunol. 177: 604-611 [Abstract] [Full Text]  
• Vlahos, R., Bozinovski, S., Jones, J. E., Powell, J., Gras, J., Lilja, A., Hansen, M. J., Gualano, R. C., Irving, L., Anderson, G. P. (2006). Differential protease, innate immunity, and NF-{kappa}B induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 290: L931-L945 [Abstract] [Full Text]  
• Parihar, R., Trotta, R., Roda, J. M., Ferketich, A. K., Tridandapani, S., Caligiuri, M. A., Carson, W. E. III (2005). Src Homology 2-Containing Inositol 5'-Phosphatase 1 Negatively Regulates IFN-{gamma} Production by Natural Killer Cells Stimulated with Antibody-Coated Tumor Cells and Interleukin-12. Cancer Res. 65: 9099-9107 [Abstract] [Full Text]  
• Pertosa, G., Simone, S., Soccio, M., Marrone, D., Gesualdo, L., Schena, F. P., Grandaliano, G. (2005). Coagulation Cascade Activation Causes CC Chemokine Receptor-2 Gene Expression and Mononuclear Cell Activation in Hemodialysis Patients. J. Am. Soc. Nephrol. 16: 2477-2486 [Abstract] [Full Text]  
• Zhou, H.-R., Jia, Q., Pestka, J. J. (2005). Ribotoxic Stress Response to the Trichothecene Deoxynivalenol in the Macrophage Involves the Src Family Kinase Hck. Toxicol Sci 85: 916-926 [Abstract] [Full Text]  
• Severgnini, M., Takahashi, S., Tu, P., Perides, G., Homer, R. J., Jhung, J. W., Bhavsar, D., Cochran, B. H., Simon, A. R. (2005). Inhibition of the Src and Jak Kinases Protects against Lipopolysaccharide-induced Acute Lung Injury. Am. J. Respir. Crit. Care Med. 171: 858-867 [Abstract] [Full Text]  
• Yan, S. R., Byers, D. M., Bortolussi, R. (2004). Role of Protein Tyrosine Kinase p53/56lyn in Diminished Lipopolysaccharide Priming of Formylmethionylleucyl- phenylalanine-Induced Superoxide Production in Human Newborn Neutrophils. Infect. Immun. 72: 6455-6462 [Abstract] [Full Text]  
• Pereira, S., Zhang, H., Takai, T., Lowell, C. A. (2004). The Inhibitory Receptor PIR-B Negatively Regulates Neutrophil and Macrophage Integrin Signaling. J. Immunol. 173: 5757-5765 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS