Tumor Suppressor p53 Inhibits Autoimmune Inflammation and Macrophage Function

  1. Shi-Jun Zheng,
  2. Salah-Eddine Lamhamedi-Cherradi,
  3. Pu Wang,
  4. Lingyun Xu and
  5. Youhai H. Chen
  1. From the Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  1. 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.

Footnotes

  • S.-J.Z. and S.-E.L.-C. contributed equally to this work.

  • S.-E.L.-C. is currently affiliated with Tanox, Houston, Texas. L.X. is currently affiliated with the Shanghai Institute of Immunology, Shanghai, China.

    • Accepted February 9, 2005.
    • Received June 29, 2004.
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