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Molecular and Cellular Biology, June 2003, p. 4026-4033, Vol. 23, No. 11
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.11.4026-4033.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of SODD in Regulation of Tumor Necrosis Factor Responses

Hidetoshi Takada,1,2 Nien-Jung Chen,1 Christine Mirtsos,1 Shinobu Suzuki,1 Nobutaka Suzuki,1 Andrew Wakeham,1 Tak W. Mak,1 and Wen-Chen Yeh1*

Advanced Medical Discovery Institute, University Health Network, Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1,1 Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan2

Received 14 November 2002/ Returned for modification 7 January 2003/ Accepted 4 March 2003

Signaling from tumor necrosis factor receptor type 1 (TNFR1) can elicit potent inflammatory and cytotoxic responses that need to be properly regulated. It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation. In this study, we demonstrate that mice lacking SODD produce larger amounts of cytokines in response to in vivo TNF challenge. SODD-deficient macrophages and embryonic fibroblasts also show altered responses to TNF. TNF-induced activation of NF-{kappa}B is accelerated in SODD-deficient cells, but TNF-induced c-Jun N-terminal kinase activity is slightly repressed. Interestingly, the apoptotic arm of TNF signaling is not hyperresponsive in the SODD-deficient cells. Together, these results suggest that SODD is critical for the regulation of TNF signaling.

* Corresponding author. Mailing address: 620 University Ave. No. 706, Toronto, Ontario, Canada M5G 2C1. Phone: (416) 204-2232. Fax: (416) 204-2278. E-mail: wyeh{at}uhnres.utoronto.ca.

Molecular and Cellular Biology, June 2003, p. 4026-4033, Vol. 23, No. 11
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.11.4026-4033.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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