A NOVEL STAT-LIKE FACTOR MEDIATES LIPOPOLYSACCHARIDE, INTERLEUKIN-1 (IL-1), AND IL-6 SIGNALING AND RECOGNIZES A GAMMA-INTERFERON ACTIVATIONSITE-LIKE ELEMENT IN THE IL1B GENE

Binding of many cytokines to their cognate receptors immediately activ ates Jak tyrosine kinases and their substrates, STAT (signal transduce rs and activators of transcription) DNA-binding proteins, The DNA bind ing targets of STATs are sequence elements related to the archetypal g amma interferon activation site, GAS, However, association of interleu kin 1 (IL-1) with Jak-STAT signaling has remained unresolved, We now r eport an element termed LILRE (lipopolysaccharide [LPS] and IL-l-respo nsive element) in the human prointerleukin 1 beta gene (IL1B) which ca n be immediately induced by either lipopolysaccharide (LPS) or IL-1 pr otein to bind a tyrosine-phosphorylated protein. This LPS- and IL-1-in duced factor (LIL factor) is recognized by an antibody raised against the N terminus of Stat1, but not by those specific for either the C te rminus of Stat1 or any other GAS-binding STAT, Phosphotyrosine (P-Tyr) specifically inhibits formation of the LIL factor-DNA complex, sugges ting the importance of P-Tyr for the DNA-binding activity, as has been found for all STAT dimers, Analysis of DNA-binding specificity demons trates that the LIL factor possesses a novel GAS-like binding activity that contrasts with those of other STATs in a requirement for a G res idue at position 8 (TTCCTGAGA), Further investigation has revealed tha t IL-6, but neither IL-4 nor gamma interferon, activates the LIL facto r. Thus, the existence of such a STAT-like factor (IL-Stat) relates th e 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, a nd IL-6 may use a common signaling pathway.