Src-regulated extracellular signal-related kinase and Syk-regulated c-Jun N-terminal kinase pathways act in conjunction to induce IL-1 synthesis in response to microtubule disruption in HL60 cells.
A microtubule reorganization is often observed during cellular contacts that are associated to IL-1 production. Here, we show that in HL60 cells, vincristine, a microtubule-disrupting agent that induces a strong production of IL-1, triggers the activation of both extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK-1). While ERK activation is rapid and transient, peaking at 10 min, the JNK1 activation is delayed and more sustained reaching a maximum at 2 h. ERK activation was blocked by CP 118556, indicating it is regulated by a Src-like kinase, while JNK1 was inhibited by piceatannol, revealing an upstream regulation by Syk. Each kind of the nonreceptor tyrosine kinase blockers efficiently inhibits the vincristine-induced IL-1 production and diminishes the level of IL-1 transcripts, indicating that the ERK and JNK pathways act coordinately to elicit the transcription of the IL-1 gene. Furthermore, we found that pertussis toxin, a blocker of Go/Gi proteins, abrogated the vincristine-induced activation of both Src and Syk. Our data support a model where the status of microtubule polymerization influences the activity of Go or Gi proteins that control, in turn, two independent Src/ERK and Syk/JNK1 cascades that are both necessary to sustain IL-1 synthesis.
Cambien
B
B
Institut National de la Santé et de la Recherche Scientifique Unite 364, Nice, France.
Millet
M A
MA
Schmid-Antomarchi
H
H
Brossette
N
N
Rossi
B
B
Schmid-Alliana
A
A
D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004792:Enzyme Precursors / Q000378:metabolism / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D018922:HL-60 Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D000072377:Syk Kinase; D013997:Time Factors; D014750:Vincristine / Q000037:antagonists & inhibitors / Q000633:toxicity; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D004792:Enzyme Precursors; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D010566:Virulence Factors, Bordetella; D014750:Vincristine; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D020962:Heterotrimeric GTP-Binding Proteins