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 interleukin 1 (IL-1) and tumor necrosis factor, stimuli which simultaneously activate different mitogen-activated protein (MAP) kinases and NF-kappaB. 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-kappaB-inducing kinase (NIK). Activation of the IL-8 promoter by either of the kinases required functional NF-kappaB 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-kappaB, 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.
Holtmann
H
H
Institute of Molecular Pharmacology, Medical School Hannover, D-30625 Hannover, Germany.
Winzen
R
R
Holland
P
P
Eickemeier
S
S
Hoffmann
E
E
Wallach
D
D
Malinin
N L
NL
Cooper
J A
JA
Resch
K
K
Kracht
M
M
D001665:Binding Sites; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000494:pharmacology*; D016209:Interleukin-8 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D000097782:NF-kappaB-Inducing Kinase
D016207:Cytokines; D016209:Interleukin-8; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000097782:NF-kappaB-Inducing Kinase