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Molecular and Cellular Biology, July 2001, p. 4544-4552, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4544-4552.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Transactivation by the p65 Subunit of NF-kappa B in Response to Interleukin-1 (IL-1) Involves MyD88, IL-1 Receptor-Associated Kinase 1, TRAF-6, and Rac1

Caroline Jefferies,1,* Andrew Bowie,1 Gareth Brady,1 Emma-Louise Cooke,2 Xiaoxia Li,3 and Luke A. J. O'Neill1

Department of Biochemistry and Biotechnology Institute, Trinity College, Dublin 2, Ireland1; Department of Cell Biology, Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom2; and Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 441953

Received 30 August 2000/Returned for modification 2 October 2000/Accepted 19 April 2001

We have examined the involvement of components of the interleukin-1 (IL-1) signaling pathway in the transactivation of gene expression by the p65 subunit of NF-kappa B. Transient transfection of cells with plasmids encoding wild-type MyD88, IL-1 receptor-associated kinase 1 (IRAK-1), and TRAF-6 drove p65-mediated transactivation. In addition, dominant negative forms of MyD88, IRAK-1, and TRAF-6 inhibited the IL-1-induced response. In cells lacking MyD88 or IRAK-1, no effect of IL-1 was observed. Together, these results indicate that MyD88, IRAK-1, and TRAF-6 are important downstream regulators of IL-1-mediated p65 transactivation. We have previously shown that the low-molecular-weight G protein Rac1 is involved in this response. Constitutively active RacV12-mediated transactivation was not inhibited by dominant negative MyD88, while dominant negative RacN17 inhibited the MyD88-driven response, placing Rac1 downstream of MyD88 on this pathway. Dominant negative RacN17 inhibited wild-type IRAK-1- and TRAF-6-induced transactivation, and in turn, dominant negative IRAK-1 and TRAF-6 inhibited the RacV12-driven response, suggesting a mutual codependence of Rac1, IRAK-1, and TRAF-6 in regulating this pathway. Finally, Rac1 was found to associate with the receptor complex via interactions with both MyD88 and the IL-1 receptor accessory protein. A pathway emanating from MyD88 and involving IRAK-1, TRAF-6, and Rac1 is therefore involved in transactivation of gene expression by the p65 subunit of NF-kappa B in response to IL-1.

* Corresponding author. Mailing address: Department of Biochemistry and Biotechnology Institute, Trinity College, Dublin 2, Ireland. Phone: 353-1-6082449. Fax: 353-1-6772400. E-mail: jefferca{at}tcd.ie.

Molecular and Cellular Biology, July 2001, p. 4544-4552, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4544-4552.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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