Signal requirements for production of luteinizing hormone releasing-hormone by human T cells.
We have previously demonstrated that both human CD4+ and CD8+ T lymphocytes produce enhanced levels of luteinizing hormone-releasing hormone (LHRH) mRNA and peptide upon stimulation with monoclonal antibody directed at the CD3 component of the T cell receptor for antigen (TCR) or mitogenic lectin. In the current study, we define the signaling pathways that control TCR-mediated LHRH production by using agents known to affect distinct signals, and compare the messenger systems required for LHRH response to other T-cell-associated activation responses, such as expression of CD69 and interleukin-2 receptor (IL-2R) molecules and production of interleukin-2 (IL-2). Results indicate that the activation of protein kinase C (PKC) is essential for LHRH production by previously nonstimulated T cells, not increased concentration of cytosolic-free calcium ([Ca2+]i). Phorbol ester (PMA), a direct activator of PKC, provoked LHRH production and cell surface expression of CD69 and IL-2R molecules by T cells, but not IL-2 synthesis. The synthesis of IL-2 by T cells required costimulation with PMA and ionomycin, a Ca2+ ionophore. Consistent with these observations, H7, an inhibitor of PKC, prevented T cells from producing LHRH upon activation with mitogen. However, LHRH production was not suppressed by HA1004, which inhibits all cyclic nucleotide-dependent protein kinases except for PKC. Genistein, a selective inhibitor of protein tyrosine kinase, blocked PMA-induced increase in LHRH production, but not CD69 and IL-2R expression, suggesting that protein tyrosine phosphorylation events distal from PKC activation may play a role in regulating LHRH response.
Mohagheghpour
N
N
Kuzell Institute for Arthritis and Infectious Diseases, California Pacific Medical Center Research Institute, San Francisco 94115, USA.
Abel
K
K
La Paglia
N
N
Emanuele
N V
NV
Azad
N
N
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis / Q000187:drug effects; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000187:drug effects; D019833:Genistein; D007987:Gonadotropin-Releasing Hormone / Q000096:biosynthesis* / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000032:analysis; D007529:Isoflavones / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D037181:Lectins, C-Type; D008297:Male; D008875:Middle Aged; D010835:Phytohemagglutinins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000099192:CD69 Antigens
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019833:Genistein; D007987:Gonadotropin-Releasing Hormone; D007376:Interleukin-2; D007529:Isoflavones; D007546:Isoquinolines; D037181:Lectins, C-Type; D010835:Phytohemagglutinins; D010879:Piperazines; D011493:Protein Kinase C; D015375:Receptors, Interleukin-2; D013755:Tetradecanoylphorbol Acetate; D000099192:CD69 Antigens