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B Kinase Complexes: Role in Activation of the IL-2 Promoter1
*
Division of Clinical Immunology and Allergy, Department of Medicine, Center for Health Sciences, Los Angeles, CA 90095;
Signal Pharmaceuticals, Inc., San Diego, CA 92121; and
Abramson Family Cancer Research Institute at the University of Pennsylvania Cancer Center, Philadelphia, PA 19104
NF-
B transcription factors play an important role in the
activation of the IL-2 gene in response to TCR ligation. The release of
NF-B factors to the nucleus requires phosphorylation and degradation
of the inhibitory -B proteins (IBs). IB
and IBß
phosphorylation is dependent on dual signaling by the TCR and the CD28
accessory receptor. This pathway involves a multisubunit IB kinase
(IKK) complex, which includes the IKK (IKK-1) and IKKß (IKK-2)
kinases. We demonstrate that stimulation of primary human
CD4+ T cells by CD3/CD28 activates two distinct endogenous
IKK complexes, a heterodimeric IKK/ß and a homodimeric IKKß
complex. IKKß overexpression in a Jurkat cell line resulted in the
formation of a constitutively active IKK complex, which was CD3/CD28
inducible. In contrast, ectopic expression of IKK assembled into a
complex with negligible IB kinase activity. Moreover, IKKß, but
not IKK, overexpression enhanced transcriptional activation of the
CD28 response element in the IL-2 promoter. Conversely, only
kinase-inactive IKKß interfered in the activation of the IL-2
promoter. Sodium salicylate, an inhibitor of IKKß, but not IKK,
activity, inhibited IL-2 promoter activation as well as IL-2 secretion
and interfered in activation of both the heterodimeric as well as the
homodimeric IKK complexes in primary CD4+ T cells. Taken
together, these data demonstrate the presence of an IKKß-mediated
signaling pathway that is activated by TCR and CD28 coligation and
regulates IL-2 promoter activity.
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