C. Bousquet et S. Melmed, Critical role for STAT3 in murine pituitary adrenocorticotropin hormone leukemia inhibitory factor signaling, J BIOL CHEM, 274(16), 1999, pp. 10723-10730
Leukemia inhibitory factor (LIF) is a pleiotropic neuroimmune cytokine that
promotes corticotroph cell differentiation and induces proopiomelanocortin
(POMC) mRNA expression and adrenocorticotropin hormone (ACTH) secretion. H
owever, molecular mechanisms for this induction remain elusive. We therefor
e developed ACTH-secreting AtT20 transformants for wild-type or mutated STA
T3, a cytokine signaling molecule, to address whether STAT3 is a determinan
t of LIF-mediated ACTH regulation. We show that these mutants act in a domi
nant negative manner by blocking endogenous STAT3 tyrosine phosphorylation
or STAT3 DNA binding. Attenuation of STAT3 activity in the dominant negativ
e AtT20 clones prevented LIF from promoting transcriptional activation of t
he POMC promoter (2.1-fold), whereas this LIF action was enhanced (7.7-fold
; p < 0.05) in wild-type STAT3-overexpressing clones in comparison to mock-
transfected cells (4.5-fold). However, wildtype or dominant negative STAT3-
overexpressing clones showed comparable (4-fold) POMC induction after treat
ment with cyclic adenosine monophosphate (cAMP), an alternate inducer of PO
MC transcription, indicating the STAT3 specificity for LIF signaling. Moreo
ver, dominant negative inactivation of STAT3 activity resulted in abrogatio
n of LIF-induced POMC mRNA levels and ACTH secretion, confirming the in viv
o role of STAT3 in LIF-mediated corticotroph action. Chemical or molecular
blockade of the mitogen-activated protein kinase pathway did not affect LIF
-mediated corticotroph function. These results indicate that STAT3 is a cri
tical intrapituitary component of the LIF-mediated neuroimmunoendocrine int
erface in corticotroph cells.