Tumor Suppressor p53 Inhibits Autoimmune Inflammation and Macrophage Function
- From the Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Address correspondence and reprint requests to Youhai H. Chen, MD, PhD, 614 BRB-II/III, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Blvd., Philadelphia, PA 19104. E-mail: yhc{at}mail.med.upenn.edu
Abstract
The tumor suppressor p53 regulates apoptosis, cell cycle, and oncogenesis. To explore the roles of p53 in autoimmunity, we studied type 1 diabetes and innate immune responses using C57BL/6 mice deficient in p53. We found that p53-deficient mice were more susceptible to streptozotocin-induced diabetes than control mice, and they produced higher levels of interleukin-1, -6, and -12. The innate immune response of p53−/− macrophages to lipopolysaccharides and γ-interferon was significantly enhanced compared with p53+/+ cells. p53−/− macrophages produced more proinflammatory cytokines and higher levels of total and phosphorylated signal transducer and activator of transcription (STAT)-1. These results indicate that p53 inhibits autoimmune diabetes and innate immune responses through downregulating STAT-1 and proinflammatory cytokines.
- DMEM, Dulbecco’s modified Eagle’s medium
- IFN-γ, γ-interferon
- IL, interleukin
- STAT, signal transducer and activator of transcription
- STZ, streptozotocin
- TNF-α, tumor necrosis factor-α
Footnotes
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S.-J.Z. and S.-E.L.-C. contributed equally to this work.
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S.-E.L.-C. is currently affiliated with Tanox, Houston, Texas. L.X. is currently affiliated with the Shanghai Institute of Immunology, Shanghai, China.
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- Accepted February 9, 2005.
- Received June 29, 2004.
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