A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene.
Binding of many cytokines to their cognate receptors immediately activates Jak tyrosine kinases and their substrates, STAT (signal transducers and activators of transcription) DNA-binding proteins. The DNA binding targets of STATs are sequence elements related to the archetypal gamma interferon activation site, GAS. However, association of interleukin 1 (IL-1) with Jak-STAT signaling has remained unresolved. We now report an element termed LILRE (lipopolysaccharide [LPS] and IL-1-responsive element) in the human prointerleukin 1beta gene (IL1B) which can be immediately induced by either lipopolysaccharide (LPS) or IL-1 protein to bind a tyrosine-phosphorylated protein. This LPS- and IL-1-induced factor (LIL factor) is recognized by an antibody raised against the N terminus of Stat1, but not by those specific for either the C terminus of Stat1 or any other GAS-binding STAT. Phosphotyrosine (P-Tyr) specifically inhibits formation of the LIL factor-DNA complex, suggesting the importance of P-Tyr for the DNA-binding activity, as has been found for all STAT dimers. Analysis of DNA-binding specificity demonstrates that the LIL factor possesses a novel GAS-like binding activity that contrasts with those of other STATs in a requirement for a G residue at position 8 (TTCCTGAGA). Further investigation has revealed that IL-6, but neither IL-4 nor gamma interferon, activates the LIL factor. Thus, the existence of such a STAT-like factor (LIL-Stat) relates the LPS and IL-1 signaling pathway to other cytokine receptor signaling pathways via the activation of STATs. Moreover, the unique DNA-binding specificity and antigenicity of this factor suggest that LPS, IL-1, and IL-6 may use a common signaling pathway.
Tsukada
J
J
Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
Waterman
W R
WR
Koyama
Y
Y
Webb
A C
AC
Auron
P E
PE
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D007375:Interleukin-1 / Q000235:genetics* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D019000:Phosphotyrosine; D011994:Recombinant Proteins / Q000494:pharmacology; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction; D013945:Thymoma; D013953:Thymus Neoplasms; D014157:Transcription Factors / Q000302:isolation & purification / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D000906:Antibodies; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D015850:Interleukin-6; C114046:LIL-Stat transcription factor; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D010748:Phosphopeptides; D010750:Phosphoproteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D019000:Phosphotyrosine; D007371:Interferon-gamma