Tatsuno I, Somogyvari-Vigh A, Mizuno K, Gottschall P E, Hidaka H, Arimura A
US-Japan Biomedical REsearch Laboratories, Tulane University Hebert Center, Belle Chasse, Louisiana 70037.
Endocrinology. 1991 Oct;129(4):1797-804. doi: 10.1210/endo-129-4-1797.
Interleukin 6 (IL-6) production was shown to be stimulated by vasoactive intestinal peptide via cAMP dependent signal transduction pathway in the pituitary. We were interested in whether other hypothalamic neuropeptides, which activate adenylate cyclase in the pituitary, also stimulate pituitary IL-6 production. Whereas vasoactive intestinal peptide was effective in stimulating pituitary IL-6 production only at concentrations of 10(-6) M or higher, pituitary adenylate cyclase activating polypeptide with 38 residues (PACAP38) and calcitonin gene-related peptide (CGRP) at concentrations from 10(-10) to 10(-9) M significantly stimulated IL-6 production. Similar effective concentrations of each peptide were required for activating adenylate cyclase, as measured by extracellular cAMP accumulation. H89, a specific inhibitor of cAMP dependent protein kinase (protein kinase A), inhibited IL-6 production stimulated by PACAP38, CGRP, and (Bu)2cAMP. However, H89 failed to inhibit the IL-6 production stimulated by lipopolysaccharide, a ligand which enhanced IL-6 production in the absence of cAMP accumulation. Two other peptides which are known to activate pituitary adenylate cyclase, corticotropin-releasing factor and GRF failed to stimulate IL-6 production in pituitary cells. Using discontinuous Percoll gradients to fractionate the pituitary cells, the greatest PACAP38-stimulated IL-6 secretion was observed in the low density fraction 1 (F1). This fraction also contained the highest percentage of folliculo-stellate (FS) cells, one of the nonhormone secreting pituitary cells. However, the largest PACAP38-induced accumulation of cAMP was observed in F4. These results suggest that the production of IL-6 stimulated by PACAP and CGRP is mediated by the adenylate cyclase/protein kinase A signal transduction system. FS cells appear to be the most likely target cell type for PACAP-induced IL-6 production. However, IL-6 producing FS cells may not be an exclusive target for PACAP in the pituitary.
研究表明，血管活性肠肽通过垂体中的cAMP依赖性信号转导途径刺激白细胞介素6（IL-6）的产生。我们感兴趣的是，其他能激活垂体腺苷酸环化酶的下丘脑神经肽是否也能刺激垂体IL-6的产生。血管活性肠肽仅在浓度为10^(-6) M或更高时才有效刺激垂体IL-6的产生，而含38个氨基酸残基的垂体腺苷酸环化酶激活多肽（PACAP38）和降钙素基因相关肽（CGRP）在浓度为10^(-10)至10^(-9) M时能显著刺激IL-6的产生。通过细胞外cAMP积累测量发现，激活腺苷酸环化酶所需的每种肽的有效浓度相似。H89是一种cAMP依赖性蛋白激酶（蛋白激酶A）的特异性抑制剂，它能抑制PACAP38、CGRP和（Bu）2cAMP刺激的IL-6产生。然而，H89未能抑制脂多糖刺激的IL-6产生，脂多糖是一种在不积累cAMP的情况下增强IL-6产生的配体。另外两种已知能激活垂体腺苷酸环化酶的肽，促肾上腺皮质激素释放因子和生长激素释放因子，未能刺激垂体细胞产生IL-6。使用不连续的Percoll梯度对垂体细胞进行分级分离，在低密度组分1（F1）中观察到最大的PACAP38刺激的IL-6分泌。该组分还含有最高比例的滤泡星状（FS）细胞，这是一种非激素分泌性垂体细胞。然而，在F4中观察到最大的PACAP38诱导的cAMP积累。这些结果表明，PACAP和CGRP刺激的IL-6产生是由腺苷酸环化酶/蛋白激酶A信号转导系统介导的。FS细胞似乎是PACAP诱导IL-6产生的最可能靶细胞类型。然而，产生IL-6的FS细胞可能不是垂体中PACAP的唯一靶细胞。
