V. Casolaro et al., INHIBITION OF NF-AT-DEPENDENT TRANSCRIPTION BY NF-KAPPA-B - IMPLICATIONS FOR DIFFERENTIAL GENE-EXPRESSION IN T-HELPER CELL SUBSETS, Proceedings of the National Academy of Sciences of the United Statesof America, 92(25), 1995, pp. 11623-11627
Activation of individual CD4(+) T cells results in differential lympho
kine expression: interleukin 2 (IL-2) is preferentially produced by T
helper type 1 (T(H)1) cells, which are involved in cell-mediated immun
e responses, whereas IL-4 is synthesized by T(H)2 cells, which are ess
ential for humoral immunity. The Ca2+-dependent factor NF-AT(p) plays
a key role in the inducible transcription of both these lymphokine gen
es, However, while IL2 expression requires the contribution of Ca2+- a
nd protein kinase C-dependent signals, we report that activation of hu
man IL4 transcription through the Ca2+-dependent pathway is diminished
by protein kinase C stimulation in Jurkat T cells, This phenomenon is
due to mutually exclusive binding of NF-AT(p) and NF-kappa B to the P
sequence, an element located 69 bp upstream of the IL4 transcription
initiation site, Human IL4 promoter-mediated transcription is dormregu
lated in Jurkat cells stimulated with the NF-kappa B-activating cytoki
ne tumor necrosis factor alpha and suppressed in RelA-overexpressing c
ells, In contrast, protein kinase C stimulation or RelA overexpression
does not affect the activity of a human IL4 promoter containing a mou
se P sequence, which is a higher-affinity site for NF-AT(p) and a lowe
r-affinity site for RelA, Thus, competition between two general transc
riptional activators, RelA and NF-AT(p), mediates the inhibitory effec
t of protein kinase C stimulation on IL4 expression and may contribute
to differential gene expression in T-H cells.