IL-3 and IL-4 activate cyclic nucleotide phosphodiesterases 3 (PDE3) and 4(PDE4) by different mechanisms in FDCP2 myeloid cells

In FDCP2 myeloid cells, IL-4 activated cyclic nucleotide phosphodiesterases PDE3 and PDE4, whereas IL-3, granulocyte-macrophage CSF (GM-CSF), and phor bol ester (PMA) selectively activated PDE4. IL-4 (not IL-3 or GM-CSF) induc ed tyrosine phosphorylation of insulin-receptor substrate-2 (IRS-2) and its association with phosphatidylinositol 3 kinase (PI3-K). TNF-alpha, AG-490 (Janus kinase inhibitor), and wortmonnin (PI3-K inhibitor) inhibited activa tion of PDE3 and PDE4 by, IL-4. TNF-alpha also blocked IL-4-induced tyrosin e phosphorylation of IRS-2, but not of STAT6. AG-490 and wortmannin, not TN F-alpha, inhibited activation of PDE4 by IL-3, These results suggested that IL-4-induced activation of PDE3 and PDE4 Has downstream of IRS-2/ PI3-K, n ot STAT6, and that inhibition of tyrosine phosphorylation! of IRS molecules might be one mechanism a whereby TNF-alpha could selectively regulate acti vities of cytokines that utilized IRS proteins as signal transducers. RO31- 7549 (protein kinase C (PKC) inhibitor) inhibited activation of PDE4 by PMA . IL-4, IL-3, and GM-CSF activated mitogen mitogen-activated protein (MAP)] kinase and protein kinase B via PI3-K signals; PMA activated only. MAP kin ase r ia PF;C signals, The MAP kinase kinase (MEK-1) inhibitor PD98059 inhi bited IL-4-, IL-3-, and PMA-induced activation of MAP kinase and PDE4, but not IL-4-induced activation of PDES. In FDCP2 cells transfected with consti tutively activated MEK, MAP kinase and PDE4, not PDE3, Here activated, Thus , in FDCP2 cells, PDE4 can be activated by overlapping. MAP kinase-dependen t pathways involving PI3-K (IL-4, IL-3, GM-CSF) or PKC (PMA), but selective activation of PDE3 by IL-4 is MAP kinase independent (but perhaps IRS-2/PI 3-K dependent).