Blind E, Knappe V, Raue F, Pfeilschifter J, Ziegler R
Department of Internal Medicine I-Endocrinology and Metabolism, University of Heidelberg, Germany.
Biochem Biophys Res Commun. 1992 Jan 15;182(1):341-7. doi: 10.1016/s0006-291x(05)80150-0.
Tumor necrosis factor alpha (TNF alpha) and parathyroid hormone-related protein (PTHrP) are both factors that have been implicated in the mechanism of hypercalcemia of malignancy. In this study we investigated the effect of TNF alpha on the PTHrP-stimulated accumulation of intracellular cyclic AMP in osteoblast-like cells. In the clonal cell line Saos-2 and in primary cell cultures from fetal rat calvaria, PTHrP-stimulated accumulation of cAMP was time- and dose-dependently inhibited by exposure to TNF alpha. Significant inhibition occurred at concentrations as low as 2 x 10(-12) M and was maximal at 1 x 10(-9) M. Inhibition was observed after 6 h and was maximal after 18 h. Inhibition by TNF alpha was probably mediated by protein kinase C, since the phorbol ester PMA mimicked the effect of TNF alpha, and the protein kinase C inhibitor H-7 completely abolished the effect of TNF alpha. In conclusion, these observations suggest a possible mechanism by which TNF alpha may modulate the effect of PTHrP on osteoblast function in the syndrome of humoral hypercalcemia of malignancy.
肿瘤坏死因子α（TNFα）和甲状旁腺激素相关蛋白（PTHrP）都是与恶性肿瘤高钙血症机制有关的因子。在本研究中，我们调查了TNFα对成骨样细胞中PTHrP刺激的细胞内环磷酸腺苷（cAMP）积累的影响。在克隆细胞系Saos-2和来自胎鼠颅骨的原代细胞培养物中，暴露于TNFα会时间和剂量依赖性地抑制PTHrP刺激的cAMP积累。在低至2×10⁻¹² M的浓度下就出现了显著抑制，在1×10⁻⁹ M时达到最大抑制。6小时后观察到抑制作用，18小时后达到最大抑制。TNFα的抑制作用可能是由蛋白激酶C介导的，因为佛波酯PMA模拟了TNFα的作用，而蛋白激酶C抑制剂H-7完全消除了TNFα的作用。总之，这些观察结果提示了一种可能的机制，通过该机制TNFα可能在恶性肿瘤体液性高钙血症综合征中调节PTHrP对成骨细胞功能的影响。
