Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine- or stress-activated signal transduction pathways

A hallmark of inflammation is the burst-like formation of certain proteins, initiated by cellular stress and proinflammatory cytokines like interleuki n 1 (IL-1) and tumor necrosis factor, stimuli which simultaneously activate different mitogen-activated protein (MAP) kinases and NF-kappa B. Cooperat ion of these signaling pathways to induce formation of IL-8, a prototype ch emokine which causes leukocyte migration and activation, was investigated b y expressing active and inactive forms of protein kinases. Constitutively a ctive MAP kinase kinase 7 (MKK7), an activator of the stress-activated prot ein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathway, induced IL-8 synthes is and transcription from a minimal IL-8 promoter. Furthermore, MKK7 synerg ized in both effects with NF-kappa B-inducing kinase (NIK). Activation of t he IL-8 promoter by either of the kinases required functional NF-kappa B an d AP-1 sites. While NIK and MKK7 did not affect degradation of IL-8 mRNA, a n active form of MKK6, which selectively activates p38 MAP kinase, induced marked stabilization of the transcript and further increased IL-8 protein f ormation induced by NIK plus MKK7. Consistently, the MAP kinase kinase kina se MEKK1, which can activate NF-kappa B, SAPK/JNK, and p38 MAP kinases, mos t potently induced IL-8 formation. These results provide evidence that maxi mal IL-8 gene expression requires the coordinate action of at least three d ifferent signal transduction pathways which cooperate to induce mRNA synthe sis and suppress mRNA degradation.