Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism.
Interleukins (IL) 1 and 6 are important cytokines that function via the activation, respectively, of the transcription factors NF-kappaB and STAT3. We have observed that a specific type of kappa B DNA sequence motif supports both NF-kappaB p65 homodimer binding and cooperativity with non-tyrosine-phosphorylated STAT3. This activity, in contrast to that mediated by kappaB 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-kappaB 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.
Yoshida
Yasuhiro
Y
New England Baptist Bone and Joint Institute, Beth Israel Deaconess Medical Center and the Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Kumar
Arvind
A
Koyama
Yoshinobu
Y
Peng
Haibing
H
Arman
Ahmet
A
Boch
Jason A
JA
Auron
Philip E
PE
D000595:Amino Acid Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology*; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D015534:Trans-Activators / Q000378:metabolism*; D051996:Transcription Factor RelA
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D016328:NF-kappa B; D011506:Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D048029:TNF Receptor-Associated Factor 6; D015534:Trans-Activators; D051996:Transcription Factor RelA; D004247:DNA