| Author |
Kral, Julia B. Saferding, Victoria Kollmann, Isabella Cheng, Paul Einwallner, Elisa Kuttke, Mario Dohnal, Alexander B. Thell, Kathrin Hoesel, Bastian Haubenwallner, Stefan Chen, Li Halfmann, Angela Sahin, Emine Dohnal, Alexander M. Brunner, Julia Schrottmaier, Waltraud C. Blüml, Stephan Schabbauer, Gernot |
| Description |
Author Affiliation: Sahin E ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Haubenwallner S ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Kuttke M ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Kollmann I ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Halfmann A ( St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria); Dohnal AM ( St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria); Dohnal AB ( St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria); Chen L ( Bio Cancer Treatment International Ltd., Hong Kong, China); Cheng P ( Bio Cancer Treatment International Ltd., Hong Kong, China); Hoesel B ( Department of Vascular Biology and Thrombosis Research, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Einwallner E ( Department of Laboratory Medicine, Medical University of Vienna, A-1090 Vienna, Austria); Brunner J ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Kral JB ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Schrottmaier WC ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Thell K ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria); Saferding V ( Department of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.); Blüml S ( Department of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.); Schabbauer G ( Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria) |
| Abstract |
The activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN(-/-) macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBPß and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity. |
