Auernhammer C J, Chesnokova V, Melmed S
Division of Endocrinology and Metabolism, Cedars-Sinai Research Institute, University of California School of Medicine, Los Angeles 90048, USA.
Endocrinology. 1998 May;139(5):2201-8. doi: 10.1210/endo.139.5.6017.
We have shown that leukemia inhibitory factor (LIF) is expressed in corticotroph cells and stimulates POMC gene expression and ACTH secretion in vivo and in vitro. We therefore examined the regulation of in vitro and in vivo pituitary LIF expression by cytokines known to stimulate the hypothalamo-pituitary-adrenal axis. In the corticotroph cell line AtT-20/D16v-F2, recombinant murine interleukin-1beta (IL-1beta; 0.1-10.0 ng/ml) caused a 5- to 10-fold increase in LIF messenger RNA (mRNA) levels. LIF mRNA expression was induced as early as 1 h, peaked at 2 h, and still persistently elevated above the baseline after 8 h. This effect of IL-1beta on LIF mRNA expression was abolished by preincubation with human IL-1 receptor antagonist (100 ng/ml) or antimurine IL-1beta antibody (10 microg/ml). Tumor necrosis factor-alpha (20 ng/ml) only modestly increased LIF mRNA, but was synergistic with IL-1beta (up to 2.5-fold). In contrast, IL-2 and IL-6 did not alter LIF mRNA. In C57BL/6 mice, i.p. injection of 100 ng IL-1beta increased plasma ACTH and corticosterone levels after 1 h (P < 0.02). In addition, pituitary LIF mRNA content was increased for up to 2 h in response to IL-1beta. In comparison to wild-type (+/+) B6D2F1 mice, LIF knockout mice with a deleted LIF gene (-/-) exhibited decreased plasma ACTH (631 +/- 61 vs. 376 +/- 50 pg/ml; P < 0.01) and corticosterone (783 +/- 85 vs. 433 +/- 51 ng/ml; P < 0.01) levels 1 h after i.p. IL-1beta administration. In conclusion, corticotroph LIF mRNA expression is specifically stimulated by IL-1beta and tumor necrosis factor-alpha. The attenuated hypothalamo-pituitary-adrenal response to IL-1beta in LIF knockout mice indicates that the effect of IL-1beta on ACTH secretion is modulated by LIF. Thus, LIF appears to function as an immune-neuroendocrine modulator signaling the hypothalamo-pituitary-adrenal axis.
我们已经证明白血病抑制因子（LIF）在促肾上腺皮质激素细胞中表达，并在体内和体外刺激阿黑皮素原（POMC）基因表达及促肾上腺皮质激素（ACTH）分泌。因此，我们研究了已知可刺激下丘脑 - 垂体 - 肾上腺轴的细胞因子对垂体LIF在体内和体外表达的调节作用。在促肾上腺皮质激素细胞系AtT - 20/D16v - F2中，重组鼠白细胞介素 - 1β（IL - 1β；0.1 - 10.0 ng/ml）使LIF信使核糖核酸（mRNA）水平增加了5至10倍。LIF mRNA表达早在1小时就被诱导，在2小时达到峰值，并且在8小时后仍持续高于基线水平。用人类IL - 1受体拮抗剂（100 ng/ml）或抗鼠IL - 1β抗体（10 μg/ml）预孵育可消除IL - 1β对LIF mRNA表达的这种作用。肿瘤坏死因子 - α（20 ng/ml）仅适度增加LIF mRNA，但与IL - 1β具有协同作用（高达2.5倍）。相比之下，IL - 2和IL - 6不改变LIF mRNA。在C57BL / 6小鼠中，腹腔注射100 ng IL - 1β 1小时后可使血浆ACTH和皮质酮水平升高（P < 0.02）。此外，响应于IL - 1β，垂体LIF mRNA含量增加长达2小时。与野生型（+/ +）B6D2F1小鼠相比，LIF基因缺失的LIF基因敲除小鼠（ - / - ）在腹腔注射IL - 1β 1小时后，血浆ACTH（631±61对376±50 pg/ml；P < 0.01）和皮质酮（783±85对433±51 ng/ml；P < 0.01）水平降低。总之，促肾上腺皮质激素细胞LIF mRNA表达受到IL - 1β和肿瘤坏死因子 - α的特异性刺激。LIF基因敲除小鼠对IL - 1β的下丘脑 - 垂体 - 肾上腺反应减弱表明IL - 1β对ACTH分泌的作用受LIF调节。因此，LIF似乎作为一种免疫 - 神经内分泌调节剂向下丘脑 - 垂体 - 肾上腺轴发出信号。
