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 tha t ate associated to IL-1 production. Here, we show that in HL60 cells, vinc ristine, 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-an d transient, peaking at 10 min, the JNK1 activation is delayed and more sus tained 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 b y piceatannol, revealing an upstream regulation by Syk. Each kind of the no nreceptor tyrosine kinase blockers efficiently inhibits the vincristine-ind uced IL-1 production and diminishes the level of IL-1 transcripts, indicati ng that the ERK and JNK pathways act coordinately to elicit the transcripti on of the IL-1 gene. Furthermore, we found that pertussis toxin, a blocker of G(o)/G(i) proteins, abrogated the vincristine-induced activation of both Src and Syk, Our data support a model where the status of microtubule poly merization: influences the activity of G(o) or G(i) proteins that control, in turn, two independent Src/ERK and Syk/JNK1 cascades that are both necess ary to sustain IL-1 synthesis.