Inhibition of T-cell antigen receptor-mediated transmembrane signaling by protein kinase C activation.
The murine T-lymphoma cell line LBRM-33 is known to require synergistic signals delivered through the antigen receptor (Ti-CD3) complex, together with interleukin 1 (IL-1), for activation of IL-2 gene expression and IL-2 production. Although 12-O-tetradecanoylphorbol-13-acetate (TPA) was capable of replacing IL-1 as an activating stimulus under certain conditions, biologic studies indicated that TPA failed to synergize with Ti-CD3-dependent stimuli under conditions in which IL-1 was clearly active. Acute exposure to TPA and other active phorbol esters resulted in a concentration-dependent inhibition of the increases in phosphoinositide hydrolysis and intracellular free Ca2+ concentration stimulated by phytohemagglutinin or anti-Ti antibodies. TPA treatment induced no direct alteration of phospholipase C enzymatic activities in LBRM-33 cells. In contrast, both Ti-CD3 cross-linkage and TPA rapidly stimulated the phosphorylation of identical CD3 complex polypeptides, presumably via activation of protein kinase C. Exposure of LBRM-33 cells to TPA resulted in a time-dependent, partial down-regulation of surface Ti-CD3 expression. Thus, TPA treatment inhibited the responsiveness of LBRM-33 cells to Ti-CD3-dependent stimuli by inducing an early desensitization of Ti-CD3 receptors, followed by a decrease in membrane receptor expression. These studies indicate that phorbol esters deliver bidirectional signals that both inhibit Ti-CD3-dependent phosphoinositide hydrolysis and augment IL-2 production in LBRM-33 cells.
Abraham
R T
RT
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905.
Ho
S N
SN
Barna
T J
TJ
Rusovick
K M
KM
McKean
D J
DJ
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D004789:Enzyme Activation; D007295:Inositol Phosphates / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007295:Inositol Phosphates; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011493:Protein Kinase C; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium