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J. Biol. Chem., Vol. 279, Issue 3, 1768-1776, January 16, 2004

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Interleukin 1 Activates STAT3/Nuclear Factor-B Cross-talk via a Unique TRAF6- and p65-dependent Mechanism^*

Yasuhiro Yoshida, Arvind Kumar, Yoshinobu Koyama, Haibing Peng, Ahmet Arman, Jason A. Boch¶, and Philip E. Auron||

From the New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115 and the Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213

Interleukins (IL) 1 and 6 are important cytokines that function via the activation, respectively, of the transcription factors NF-B and STAT3. We have observed that a specific type of B DNA sequence motif supports both NF-B p65 homodimer binding and cooperativity with non-tyrosine-phosphorylated STAT3. This activity, in contrast to that mediated by B DNA motifs that do not efficiently bind p65 homodimers, is shown to be uniquely dependent upon signal transduction through the carboxyl terminus of TRAF6. Furthermore, STAT3 and p65 are shown to physically interact, in vivo, and this interaction appears to inhibit the function of "classical" STAT3 GAS-like binding sites. The distinct p50 form of NF-B is also shown to interact with STAT3. However, in contrast to p65, p50 cooperates with STAT3 bound to GAS sites. These data argue for a novel transcription factor cross-talk mechanism that may help resolve inconsistencies previously reported regarding the mechanism of IL-1 inhibition of IL-6 activity during the acute-phase response.

Received for publication, October 20, 2003

^* This work was supported in part by National Institutes of Health Grants CA68544 and AI44122 (to P. E. A.). 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.

^¶ Recipient of an institutional dentist scientist award from the National Institutes of Health.

^|| To whom correspondence should be addressed: Dept. of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, W1142 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261. Tel.: 412-383-9989; Fax: 412-624-1401; E-mail: auron{at}pitt.edu.

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