A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation

In the present study we examined in more detail the dual role of the c-JUN N-terminal kinase (JNK) and p38 stress-activated protein kinase pathways in mediating apoptosis or cellular activation in hematopoietic cells. Growth factor deprivation of the erythroleukemic cell line TF-1 led to apoptosis w hich was associated with an enhanced activity of JNK and p38 and immediate dephosphorylation of the extracellular signal-regulated kinases (ERKs). Enh anced activity of p38 and JNK was not only observed during apoptosis but al so in TF-1 cells stimulated with IL-1. IL-1 rescued TF-1 cells from apoptos is. In this case, the upregulation of p38 and JNK was associated with an en hanced activity of ERK. By using SB203580, a specific inhibitor of the p38 signaling pathway, it was demonstrated that p38 plays a pivotal role in the apoptotic process. SB203580 repressed the apoptotic process to a large ext ent. In contrast, PD98059, a specific inhibitor of the ERK pathway, counter acted the suppressive effects of SB203580 and IL-1 on the apoptotic process indicating that the protective effect of SB203580 and IL-1 might be the re sult of a shift in the balance between the ERK1/2 and p38/JNK route. This w as also supported by experiments with TF-1 cells overexpressing the Shc pro tein that demonstrated a significantly lower percentage of apoptotic cells, which coincided with higher ERK activity. Finally, the IL-1 and SB203580-m ediated effects were associated with an enhanced nuclear factor-kappa B (NF -kappa B) and activator protein-1 (AP-1) binding activity, which could also be blocked by PD98059. These data demonstrate a dual function of the p38 p athway whereby other factors, such as ERK kinases, AP-1 and NF-kappa B, mig ht determine the final cellular response.