INTERLEUKIN-6 INDUCTION BY TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-1 IN HUMAN FIBROBLASTS INVOLVES ACTIVATION OF A NUCLEAR FACTOR BINDING TO A KAPPA-B-LIKE SEQUENCE

Using variable-length deletion constructs of the 5'-flanking region of the human interleukin-6 (IL-6) gene linked to the chloramphenicol acetyltransferase gene, we showed that the region from positions -109 to -50 mediated the bulk of the response to tumor necrosis factor (TNF) or interleukin-1 (IL-1), while it was less responsive to forskolin. DNA mobility shift assays and DNase I footprinting analysis identified a nuclear protein from TNF- or IL-1-treated fibroblasts that bound to a region comprising a κB-like element located between positions -72 and -63 on the IL-6 gene. On the basis of these and other experiments, we conclude that TNF and IL-1 apparently activate IL-6 gene expression by closely related mechanisms involving activation of a NF- κB-like factor, whereas the pathway of IL-6 induction by forskolin is, in part, different.