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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-
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-
B-inducing kinase (NIK).
Activation of the IL-8 promoter by either of the kinases required
functional NF-
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-
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-Stra
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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