Analysis of interleukin (IL)-1 beta and transforming growth factor (TGF)-beta-induced signal transduction pathways in IL-2 and TGF-beta secretion andproliferation in the thymoma cell line EL4.NOB-1

In the present study we investigated the interleukin (IL)-1 beta and transf orming growth factor-beta(1) (TGF-beta(1))-mediated proliferation, and prod uction of IL-2 and TGF-beta, in the murine T-cell line, EL4.NOB-1. This cel l line is resistant to TGF-beta concerning growth arrest but not autoinduct ion or suppression of IL-1-induced IL-2 production. When cocultured with IL -1 beta, TGF-beta showed growth-promoting activity that could be antagonize d by adding the phosphatidyl choline-dependent phospholipase C (PC-PLC) inh ibitor, D609. Using specific enzyme inhibitors of protein kinases (PK) C an d A, mitogen-activated protein kinase (MAPK), phospholipase A(2) (PLA(2)), phosphatidylinositol-dependent (PI)-PLC and PC-PLC, we showed that IL-1 bet a-induced IL-2 synthesis was dependent on all investigated kinases and phos pholipases, except PC-PLC. TGF-beta(1) was able to inhibit IL-2 synthesis b y the activation of PKA and MAPK. The same kinases are involved in TGF-beta autoinduction that is accompanied by a secretion of the active but not the latent growth factor and is antagonized by IL-1 beta. Addition of the PI-P LC inhibitor, ET180CH(3), or the PLA2 inhibitor (quinacrine) alone, resulte d in secretion of latent TGF-beta and, in the case of ET180CH(3), active TG F-beta. These data implicate a role for PI-PLC and PLA(2) in the control of latency and secretion. Analysis of specific tyrosine activity and c-Fos ex pression showed synergistic but no antagonistic effects. These events are t herefore not involved in IL-1 and TGF-beta-regulated IL-2 and TGF-beta prod uction, but might participate in IL-1/TGF-beta-induced growth promotion.