HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Yoshimi, R. Articles by Ozato, K. PubMed PubMed Citation Articles by Yoshimi, R. Articles by Ozato, K.

Gene Disruption Study Reveals a Nonredundant Role for TRIM21/Ro52 in NF-B-Dependent Cytokine Expression in Fibroblasts¹

Ryusuke Yoshimi^*, Tsung-Hsien Chang^*, Hongsheng Wang, Toru Atsumi^*, Herbert C. Morse, III^2, and Keiko Ozato^2,*

^* Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

The tripartite motif (TRIM) family member, TRIM21, is an E3 ubiquitin ligase for IFN regulatory factor (IRF)3 and IRF8 that functions in both innate and acquired immunity. It is also an autoantigen known as Ro52/SS-A. The function of TRIM21 in vivo, however, has remained elusive. We generated Trim21^–/– mice with the Trim21 gene replaced by an enhanced GFP (EGFP) reporter. EGFP expression analyses showed that Trim21 was widely expressed in many tissues, with the highest levels in immune cells. Studies of Trim21^–/– embryonic fibroblasts demonstrated that TLR-mediated induction of proinflammatory cytokines, including IL-1β, IL-6, TNF-, and CXCL10, was consistently up-regulated relative to wild-type cells. Reporter analyses demonstrated that TLR-mediated NF-B activation was higher in Trim21^–/– cells than in wild-type cells, most likely accounting for their enhanced cytokine expression. In contrast, functional analyses of immune cells from Trim21^–/– mice revealed no abnormalities in their composition or function, even though ubiquitylation of IRF3 and IRF8 was impaired. These results suggested possible redundancies in activities mediated by TRIM21. In keeping with this concept, we found that a number of TRIM family members were up-regulated in Trim21^–/– cells. Taken together, these findings demonstrate that TRIM21 plays a previously unrecognized role in the negative regulation of NF-B-dependent proinflammatory cytokine responses, and suggest that multiple TRIM proteins contribute to the maintenance of functional equilibrium in inflammatory responses, in part through functional redundancy.

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 the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases. R.Y. and T.A. were supported in part by the Japan Society for the Promotion of Science Research Fellowship for Japanese Biomedical and Behavioral Researchers at the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Keiko Ozato, Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Building 6, Room 2A01, 6 Center Drive, Bethesda, MD 20892-2753; E-mail address: ozatok{at}nih.gov or Dr. Herbert C. Morse III, Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Twinbrook I, Room 1421, 5640 Fishers Lane, Rockville, MD 20852; E-mail address: hmorse{at}niaid.nih.gov

³ Abbreviations used in this paper: TRIM, tripartite motif; BM, bone marrow; BMDC, BM-derived dendritic cell; BMM, BM-derived macrophage; CBA, cytometric bead array; cDC, conventional dendritic cell; DC, dendritic cell; DN, double negative; EF, embryonic fibroblast; EGFP, enhanced GFP; FOL, follicular; IKK, IB kinase; IRF, IFN regulatory factor; KLH, keyhole limpet hemocyanin; LN, lymph node; MDA5, melanoma differentiation-associated gene 5; MFI, mean fluorescence intensity; MZ, marginal zone; NDV, Newcastle disease virus; NP, (4-hydroxy-3-nitrophenyl) acetyl; pDC, plasmacytoid DC; qPCR, quantitative real-time RT-PCR; RIG-I, retinoic acid-inducible gene I; SLE, systemic lupus erythematosus; SP, single positive; T, transitional; TRAF6, TNF receptor-associated factor 6.

⁴ The online version of this article contains supplemental material.

This article has been cited by other articles:

				S. Bolland and A. Garcia-Sastre Vicious circle: systemic autoreactivity in Ro52/TRIM21-deficient mice J. Exp. Med., August 3, 2009; 206(8): 1647 - 1651. [Abstract] [Full Text] [PDF]