INTERLEUKIN-1-INDUCIBLE EXPRESSION OF GRO-BETA VIA NF-KAPPA-B ACTIVATION IS DEPENDENT UPON TYROSINE KINASE SIGNALING

Interleukin-1 (IL-1) induces programmed growth arrest in human melanom a cells, A375-C6. IL-1 action in these cells is associated with induct ion of a cell type-specific immediate-early (IE) gene expression progr am characterized by strong, rapid, and sustained induction of gro-alph a and gro-beta, but transient induction of c-jun, IRG-9, and NAK-1, an d lack of induction of c-myc. With the exception of gro-alpha and gro- beta, these IE genes are also associated with growth-stimulatory respo nses in the melanoma cells, suggesting that the gro-genes may play key roles in the growth arrest action of the cytokine. To elucidate the e arly intracellular signals associated with IL-1 action, we are studyin g the second messenger signals and transcription factors required for induction of gro-genes. Here, we present evidence that IL-1-inducible gro-gene expression is dependent on tyrosine kinase signaling. Using g el retardation and transient expression assays, we show that IL-1 caus es protein tyrosine phosphorylation-dependent activation of NF-kappaB enhancer binding protein, which then induces transcription of the gro- genes via an NF-kappaB site located 76 base pairs upstream from the ca p site. IL-1-activated protein tyrosine phosphorylation is also requir ed for gro-gene induction in human cervical carcinoma cells, HeLa; hum an fibroblast cells, WI-38; and mouse fibroblast cells, L929. Thus, in diverse cell types, IL-1 induces gro-genes via tyrosine kinase-depend ent signals.