(-)-Indolactam V-induced mitogenesis in human fetal/neonatal and adult T cells: lower response of neonatal cells and possible regulatory role of monocytes in protein kinase C-mediated pathways.
(-)-Indolactam V (ILV) is a synthetic analog of the teleocidins, a newly described class of tumor promoters. Here we describe the mitogenic and comitogenic effect of (-)-ILV on human adult and fetal/neonatal (cord) lymphocytes. (-)-ILV induced proliferation in a dose-dependent manner, with optimal concentrations between 2.6 and 5.2 microM. Cord lymphocytes gave significantly lower (-)-ILV responses compared to the corresponding a2ult cells (50-60% lower at optimal mitogenic doses). The mitogenic action of (-)-ILV was apparently independent of the presence of adherent monocytes. H-7, a relatively specific protein kinase (PK) C inhibitor, and H-8, a less specific PK inhibitor, suppressed (-)-ILV-induced proliferation by 54 and 36%, respectively. Suboptimal concentrations of (-)-ILV were strongly mitogenic for both adult and cord lymphocytes when added together with calcium ionophore A23187, phytohemagglutinin, or the anti-T cell receptor monoclonal antibodies OKT3 and TCR1. In adult cells, the synergistic effect decreased with increasing concentrations of (-)-ILV or/and the other comitogens, and was, in most (> 60%) cases, converted to inhibition at the combination of optimal doses. The inhibition was invariably reversed by depletion of monocytes. In contrast, among cord lymphocytes (-)-ILV and OKT3 or TCR-1 showed strong cooperative effect at all concentrations tested. The (-)-ILV hyporesponsiveness and distinct comitogenic pattern of cord lymphocytes, together with the previously described lower cord cell response to phorbol ester TPA, suggest functional differences in signal transduction mechanisms between cord (naive) and adult (memory) T cells, possibly at the level of monocytes.
Papadogiannakis
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Department of Pathology, Karolinska Institute, Huddinge University Hospital, Sweden.
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000001:Calcimycin / Q000494:pharmacology; D005333:Fetus; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007231:Infant, Newborn; D007546:Isoquinolines / Q000494:pharmacology; D007769:Lactams / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D009000:Monocytes / Q000502:physiology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects*
D007211:Indoles; D007546:Isoquinolines; D007769:Lactams; D010835:Phytohemagglutinins; D010879:Piperazines; D011948:Receptors, Antigen, T-Cell; D000001:Calcimycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043969:indolactam V; D011493:Protein Kinase C