An inhibitor of PI3-K differentially affects proliferation and IL-6 protein secretion in normal and leukemic myeloid cells depending on the stage of differentiation

Objective. In this study, we examined the involvement of the phosphatidylin ositol 3-kinase (PI3-K) and p70S6 kinase signal transduction pathway in the interleukin-1 (IL-1)-mediated proliferation and cytokine production by nor mal and leukemic myeloid cells. Materials and Methods. Total AML blast populations, early progenitor (CD34( +)/CD36(-)) cells, and more differentiated (CD34(-)/CD36(+)) cells were tre ated with the PI3-K inhibitor Ly294002 and p70S6K inhibitor rapamycin, The effects on proliferation, IL-6 protein secretion, and intracellular signali ng cascades were determined and compared with normal CD34(+) cells and mono cytes. Results. The function of the PI3-K pathway was dependent on the differentia tion state of the AML cell population. In immature blasts, the IL-1-induced proliferation was strongly inhibited by Ly294002, and rapamycin, without a distinct effect on IL-6 protein production. In contrast, in mature monocyt ic blast cells inhibition of the PI3-K signaling route had a stimulatory ef fect on IL-6 protein secretion. Interestingly, these findings were not spec ifically linked to the malignant counterpart but were also observed with no rmal CD34(+) sorted cells vs mature monocytes, Evidence is provided that th e Ly294002-induced increase in IL-6 protein secretion is linked to the cAMP dependent signaling pathway and not to changes in the phosphorylation of E RK or p38, However, although the enhanced IL-6 protein secretion is cAMP de pendent, it was not found to be mediated by protein kinase A (PKA) or by th e GTP-ase Rap1. Conclusion, This study indicates that inhibition of the PI3-K signaling pat hway has an inhibitory effect on cell proliferation but a stimulatory effec t on IL-6 expression mediated by a cAMP-dependent but PKA-independent route . (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.