Regulation of interleukin-2 receptor alpha chain expression and nuclear factor.kappa B activation by protein kinase C in T lymphocytes. Autocrine role of tumor necrosis factor alpha.
The regulation of interleukin-2 receptor alpha chain (IL-2R alpha) expression and nuclear factor (NF) activation by protein kinase C (PKC) in resting T cells, has been studied. Treatment of human resting T cells with phorbol esters strongly induced the expression of IL-2R alpha and the activation of NF.kappa B. This activation was due to the translocation of p65 and c-Rel NF.kappa B proteins from cytoplasmic stores to the nucleus, where they bound the kappa B sequence of the IL-2R alpha promoter either as p50.p65 or as p50.c-Rel heterodimers. Interestingly, all of those events were largely indirect and mediated by endogenously secreted tumor necrosis factor alpha (TNF alpha), as they were strongly inhibited by a neutralizing anti-TNF alpha monoclonal antibody. Furthermore, cyclosporin A, which blocked TNF alpha production induced by PKC, strongly inhibited IL-2R alpha and NF.kappa B activation. The addition of either TNF alpha or IL-2 partially recovered cyclosporin A-induced IL-2R alpha inhibition, but only TNF alpha completely recovered NF.kappa B activation. Those results indicate that, in resting T cells, PKC activation has only a triggering role, whereas the endogenously secreted TNF alpha plays an essential role in the quantitative control of the expression of IL-2R alpha chain or NF.kappa B activation.
Pimentel-Muiños
F X
FX
Centro de Biología Molecular, Universidad Autonoma Madrid, Spain.
Mazana
J
J
Fresno
M
M
D000470:Alkaloids / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004247:DNA; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D019311:Staurosporine; D013601:T-Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000470:Alkaloids; D016328:NF-kappa B; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D015240:Phorbol 12,13-Dibutyrate; D016572:Cyclosporine; D004247:DNA; D011493:Protein Kinase C; D019311:Staurosporine