Kariagina Anastasia, Zonis Svetlana, Afkhami Mahta, Romanenko Dmitry, Chesnokova Vera
Cedars-Sinai Medical Center and David Geffen School of Medicine at University of California, Los Angeles, CA, USA.
Am J Physiol Endocrinol Metab. 2005 Nov;289(5):E857-63. doi: 10.1152/ajpendo.00577.2004. Epub 2005 Jun 28.
Leukemia inhibitory factor (LIF) is a pleiotropic cytokine belonging to the gp130 family. LIF is induced peripherally and within the brain during inflammatory or chronic autoimmune diseases and is a potent stimulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here we investigated the role of LIF in mediating glucocorticoid receptor (GR) expression in the HPA axis. LIF treatment (3 microg/mouse, i.p.) markedly decreased GR mRNA levels in murine hypothalamus (5-fold, P < 0.01) and pituitary (1.7-fold, P < 0.01) and downregulated GR protein levels. LIF decreased GR expression in murine corticotroph cell line AtT20 within 2 h, and this effect was sustained for 8 h after treatment. LIF-induced GR mRNA reduction was abrogated in AtT20 cells overexpressing dominant-negative mutants of STAT3, indicating that intact JAK-STAT signaling is required to mediate LIF effects on GR expression. Conversely, mice with LIF deficiency exhibited increased GR mRNA levels in the hypothalamus and pituitary (3.5- and 3.5-fold, respectively; P < 0.01 for both) and increased GR protein expression when compared with wild-type littermates. The suppressive effects of dexamethasone on GR were more pronounced in LIF-null animals. These data suggest that LIF maintains the HPA axis activation by decreasing GR expression and raise the possibility that LIF might contribute to the development of central glucocorticoid resistance during inflammation.
白血病抑制因子（LIF）是一种属于gp130家族的多效性细胞因子。在炎症或慢性自身免疫性疾病期间，LIF在外周和脑内被诱导产生，并且是下丘脑-垂体-肾上腺（HPA）轴的强效刺激物。在此，我们研究了LIF在介导HPA轴中糖皮质激素受体（GR）表达方面的作用。LIF处理（3微克/小鼠，腹腔注射）显著降低了小鼠下丘脑（5倍，P < 0.01）和垂体（1.7倍，P < 0.01）中GR mRNA水平，并下调了GR蛋白水平。LIF在2小时内降低了小鼠促肾上腺皮质激素细胞系AtT20中的GR表达，并且该效应在处理后持续8小时。在过表达STAT3显性负性突变体的AtT20细胞中，LIF诱导的GR mRNA减少被消除，这表明完整的JAK-STAT信号传导是介导LIF对GR表达影响所必需的。相反，与野生型同窝小鼠相比，LIF缺陷小鼠的下丘脑和垂体中GR mRNA水平升高（分别为3.5倍和3.5倍；两者P < 0.01），并且GR蛋白表达增加。地塞米松对GR的抑制作用在LIF基因敲除动物中更为明显。这些数据表明，LIF通过降低GR表达来维持HPA轴的激活，并增加了LIF可能在炎症期间促成中枢糖皮质激素抵抗发展的可能性。
