Cr. Yu et al., CHARACTERIZATION OF CYTOKINE DIFFERENTIAL INDUCTION OF STAT COMPLEXESIN PRIMARY HUMAN T-CELL AND NK-CELL, Journal of leukocyte biology, 64(2), 1998, pp. 245-258
Cytokines IL-2, IL-4, IL-6, IL-7, IL-12, and IL-15 are hey regulators
of human peripheral blood T and NK cell activation and differentiation
but the precise mechanisms that give rise to their differential activ
ities within these cells are not clear. Recent studies reveal that a f
amily of transcription factors, signal transducers and activators of t
ranscription (STATs) directly mediate many cytokine signals. We analyz
ed the activation of STATs in primary human T and NK cells by a variet
y of specific cytokines. We demonstrate that IL-12 induces STAT4 only
in freshly isolated primary NK cells, hut not in primary T cells, cons
istent with the lack of the IL-12 receptor in resting T cells. hi cont
rast, IL-4 induces different C epsilon GAS DNA-protein binding complex
es in both T and NIC cells. Moreover, IL-4 costimulation T,idl IL-2 or
IL-12 does not alter their own preferential GAS-like DNA binding patt
erns when C epsilon-, Fc gamma RI-, and SIE GAS motif containing oligo
nucleotide probes are compared, suggesting that induction of GAS-like
DNA-protein binding complexes by IL-2, IL-4, and IL-12 is highly selec
tive and represents one important factor in determining specific gene
activation. In addition, IL-6 and IL-2 synergistically induce homo- an
d heterodimerized STAT1 alpha and STAT3 in both NK and T cells, consis
tent with their reported synergism in modulating perforin gene express
ion. We further demonstrated that IL-2, -7, and. -15 induce multiple S
TAT proteins, including STAT5a, STAT5b, STAT1 alpha, STAT3, and anothe
r unidentified Fc gamma RI GAS DNA-binding protein. Finally, we observ
ed that activated STAT5a and STAT5b proteins form distinct Fc gamma RI
GAS binding patterns in T and NK cells, suggesting that they might ha
re different roles in gene regulation. Our data provide evidence that
the differential responses in gene expression and cell activation seen
in primary Nh and T cells on direct stimulation with different cytoki
nes may be a direct result of distinct activation of STAT transcriptio
n factors.