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NF-B p50/p65 Affects the Frequency of Ly49 Gene Expression by NK Cells^1,2,3

Véronique Pascal^*, Neera R. Nathan^*, Estefania Claudio, Ulrich Siebenlist and Stephen K. Anderson^4,*,

^* Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702; Basic Research Program, SAIC-Frederick Inc, Frederick, MD 21702; and Immune Activation Section, Laboratory of Immune Regulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

In mice, acquisition of Ly49 receptors characterizes one of the developmental stages of NK cells. We previously described a novel Ly49 promoter, Pro1, involved in Ly49 gene regulation in immature NK cells. Pro1 transcriptional activity requires a NF-B binding site; however, only NF-B/p50 binding to this element was observed. Cotransfection of NF-B/p65 with Ly49g Pro1 in LNK cells induced a decrease in the transcriptional activity of the core promoter. Moreover, decreasing NF-B/p65 protein expression by RNA interference increases Pro1 transcriptional activity. A high rate of NF-B/p65 degradation in LNK cells correlates with Pro1 activity, since treatment with the proteasome inhibitor MG132 increased levels of NF-B/p65 protein and decreased Pro1 activity. In addition, analysis of the Ly49 repertoire in NF-B/p50 null mice reveals a decrease in the proportion of NK cells expressing a given Ly49 molecule. The defect in Ly49 expression is observed in the bone marrow and the spleen with a similar altered pattern of developmental stages in each tissue. The frequency of Ly49 expression in NF-B/p52 null mice is slightly increased, indicating the specific role of NF-B/p50 in Ly49 gene activation. These results suggest that NF-B p50/p65 plays a major role in the initiation of Ly49 gene expression in NK cells.

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¹ This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute and the National Institute of Health under Contract DHHS N01-C0-12400.

² The contents of this publication do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

³ By acceptance of this article, the publisher or recipient acknowledges the right of the U.S. government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

⁴ Address correspondence and reprint requests to Dr. Stephen K. Anderson, National Cancer Institute-Frederick, Building 560, Room 31-93, Frederick, MD 21702. E-mail address: andersonst{at}mail.nih.gov

⁵ Abbreviations used in this paper: BM, bone marrow; IKK, IB kinase; MNC, mononuclear cell; WT, wild type; LT, lymphotoxin; KO, knockout.