Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Enzyme Activation / drug effects
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Enzyme Activation / immunology
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Enzyme Precursors / metabolism
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Enzyme Precursors / physiology*
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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HL-60 Cells
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Heterotrimeric GTP-Binding Proteins / metabolism
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Humans
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Interleukin-1 / biosynthesis*
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Intracellular Signaling Peptides and Proteins
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JNK Mitogen-Activated Protein Kinases
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Microtubules / drug effects
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Microtubules / enzymology
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Microtubules / immunology
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Microtubules / metabolism*
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Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinases / physiology*
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Pertussis Toxin
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Protein-Tyrosine Kinases / metabolism
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Protein-Tyrosine Kinases / physiology*
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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Syk Kinase
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Time Factors
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Vincristine / antagonists & inhibitors
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Vincristine / toxicity
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Virulence Factors, Bordetella / pharmacology
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src-Family Kinases / metabolism
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src-Family Kinases / physiology*
Substances
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Enzyme Precursors
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Interleukin-1
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Intracellular Signaling Peptides and Proteins
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Virulence Factors, Bordetella
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Vincristine
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Pertussis Toxin
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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src-Family Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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GTP-Binding Protein alpha Subunits, Gi-Go
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Heterotrimeric GTP-Binding Proteins