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Translational Regulation of Autoimmune Inflammation and Lymphoma Genesis by Programmed Cell Death 4¹

Anja Hilliard^*, Brendan Hilliard^*, Shi-Jun Zheng^2,*, Honghong Sun^*, Takashi Miwa, Wenchao Song, Rüdiger Göke and Youhai H. Chen^3,*

^* Department of Pathology and Laboratory Medicine and Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and University of Marburg, Marburg, Germany

Both inflammatory diseases and cancer are associated with heightened protein translation. However, the mechanisms of translational regulation and the roles of translation factors in these diseases are not clear. Programmed cell death 4 (PDCD4) is a newly described inhibitor of protein translation. To determine the roles of PDCD4 in vivo, we generated PDCD4-deficient mice by gene targeting. We report here that mice deficient in PDCD4 develop spontaneous lymphomas and have a significantly reduced life span. Most tumors are of the B lymphoid origin with frequent metastasis to liver and kidney. However, PDCD4-deficient mice are resistant to inflammatory diseases such as autoimmune encephalomyelitis and diabetes. Mechanistic studies reveal that upon activation, PDCD4-deficient lymphocytes preferentially produce cytokines that promote oncogenesis but inhibit inflammation. These results establish that PDCD4 controls lymphoma genesis and autoimmune inflammation by selectively inhibiting protein translation in the immune system.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (AI50059, AI055934, and AI55934).

² Current address: China Agricultural University, Beijing, China.

³ Address correspondence and reprint requests to Dr. Youhai H. Chen, 614 BRB-II/III, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104. E-mail address: yhc{at}mail.med.upenn.edu

⁴ Abbreviations used in this paper: 4E-BPs, 4E-binding proteins; eIF, eukaryotic initiating factors; 5'UTR, 5' untranslated regions; PDCD4, programmed cell death 4; ES cells, embryonic stem cells; STZ, streptozotocin; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein.

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