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Molecular and Cellular Biology, October 1999, p. 6742-6753, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Induction of Interleukin-8 Synthesis Integrates Effects on Transcription and mRNA Degradation from at Least Three Different Cytokine- or Stress-Activated Signal Transduction Pathways

Helmut Holtmann,1 Reinhard Winzen,1 Pamela Holland,2 Solveig Eickemeier,1 Elke Hoffmann,1 David Wallach,3 Nikolai L. Malinin,3 Jonathan A. Cooper,2 Klaus Resch,1 and Michael Kracht1,*

Institute of Molecular Pharmacology, Medical School Hannover, D-30625 Hannover, Germany1; Fred Hutchinson Cancer Research Center, Seattle, Washington 981092; and Department of Membrane Research and Biophysics, The Weizmann Institute of Sciences, 76100 Rehovot, Israel3

Received 10 February 1999/Returned for modification 5 March 1999/Accepted 23 June 1999

A hallmark of inflammation is the burst-like formation of certain proteins, initiated by cellular stress and proinflammatory cytokines like interleukin 1 (IL-1) and tumor necrosis factor, stimuli which simultaneously activate different mitogen-activated protein (MAP) kinases and NF-kappa B. Cooperation of these signaling pathways to induce formation of IL-8, a prototype chemokine which causes leukocyte migration and activation, was investigated by expressing active and inactive forms of protein kinases. Constitutively active MAP kinase kinase 7 (MKK7), an activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathway, induced IL-8 synthesis and transcription from a minimal IL-8 promoter. Furthermore, MKK7 synergized in both effects with NF-kappa B-inducing kinase (NIK). Activation of the IL-8 promoter by either of the kinases required functional NF-kappa B and AP-1 sites. While NIK and MKK7 did not affect degradation of IL-8 mRNA, an active form of MKK6, which selectively activates p38 MAP kinase, induced marked stabilization of the transcript and further increased IL-8 protein formation induced by NIK plus MKK7. Consistently, the MAP kinase kinase kinase MEKK1, which can activate NF-kappa B, SAPK/JNK, and p38 MAP kinases, most potently induced IL-8 formation. These results provide evidence that maximal IL-8 gene expression requires the coordinate action of at least three different signal transduction pathways which cooperate to induce mRNA synthesis and suppress mRNA degradation.

* Corresponding author. Mailing address: Institute of Molecular Pharmacology, Medical School Hannover, Carl-Neuberg-Strabeta e 1, D-30625 Hannover, Germany. Phone: 0049-511-532-2800. Fax: 0049-511-532-4081. E-mail: Kracht.Michael{at}MH-Hannover.de.

Molecular and Cellular Biology, October 1999, p. 6742-6753, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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