The soluble interleukin 6 receptor alpha is an agonistic molecule of interleukin 6 (IL-6) and is important in the biology of multiple myeloma. More precisely, it potentiates the deleterious effects of IL-6 during tumour progression, facilitating angiogenesis and bone resorption. Because the mechanisms involved in the shedding of the interleukin 6 receptor alpha (IL-6Ralpha) in multiple myeloma are not known, we have investigated them in the XG-6 human myeloma cell line. Here we provide evidence that PMA-induced IL-6Ralpha shedding is controlled by a metalloproteinase and by protein kinase C (PKC) isoenzymes that do not require Ca(2+) for their activation. We show that XG-6 cells express PKC-delta, -eta and -zeta isoenzymes. However, after stimulation with PMA, only PKC-delta and PKC-eta are activated, as shown by their translocation to the membrane. Treatment with PMA induces an increase in PKC-delta phosphorylation in its active loop. In addition, by using rottlerin, a specific inhibitor of PKC-delta, we demonstrate that PKC-delta is involved in the PMA-induced shedding of IL-6Ralpha. With the use of UO126, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway, we show that the PMA-induced IL-6Ralpha shedding is mediated in part by the MAPK pathway. Finally, whereas GF109203X, a general PKC inhibitor, inhibits the activation of ERK1/2 (extracellular signal-regulated protein kinase 1/2), rottlerin has no inhibitory effect, indicating that the Ras/MAPK activation is PKC-dependent but PKC-delta-independent. Taken together, these results suggest that the PMA-induced shedding of IL-6Ralpha is mediated by a PKC isoenzyme network.