MECHNSMS OF STEROID INHIBITION OF MICROBIAL PHAGOCYTOSIS

糖皮质激素是有效的免疫抑制剂。 的 这些药物发挥其有害作用的机制 很复杂 与我们对类固醇作用的了解相反， 淋巴细胞功能，很少有人知道的调制 巨噬细胞的功能。 因此，从长远来看， 该研究领域的目标是调查直接影响 糖皮质激素和其他免疫药理学药物对 巨噬细胞的功能如吞噬作用、抗原呈递 和杀肿瘤的能力 这项研究提出， 应用范围仅限于检验以下假设 来解释酵母菌吞噬作用的抑制 在地塞米松处理的小鼠驻留的培养物中的酿酒酵母 腹腔巨噬细胞 的潜在机制 糖皮质激素治疗中酵母摄入抑制 巨噬细胞培养物的特征如下：（1）它是 由“PIP”（一种类固醇诱导的吞噬抑制剂）介导 蛋白质，这是难以区分的脂皮质素，类固醇 诱导磷脂酶调节蛋白;（2）它需要活性 PIP活性大分子代谢抑制酵母 （3）它是通过实现和维持 有效PIP浓度;（4）受效应子调节 调节磷脂酶和蛋白激酶的分子 （5）直接或间接的;（6） 类固醇抑制内吞作用的机制 在其他模型系统中;最后，（6）它不干扰 吞噬细胞暴露于这些类固醇的杀菌能力。 因此，具体目标包括：（1）隔离和 生物化学表征PIP用于与脂皮质素比较，（2） 研究PIP表达是否需要从头RNA， 蛋白质生物合成，（3）将PIP浓度与 抑制反应的大小，（4）探索PIP是否 活性被刺激脂质的物质阻断或逆转 （5）确定PIP是否被诱导并在其他细胞中起作用， 内吞系统，以及（6）确定PIP活性是否 杀微生物的 实现这些具体目标将提供新的 深入了解类固醇诱导PIP的机制 抑制了巨噬细胞非常重要的功能 吞噬作用 这些新知识将来可能会得到应用 研究旨在分离有益的抗炎 糖皮质激素的有害作用 新的或新的组合的免疫抑制作用 化疗-免疫方案。

Glucocorticoids are potent immunosuppressive agents. The mechanisms by which these drugs exert their detrimental effects are complex. In contrast to our knowledge of steroid action on lymphocyte functions, very little is known about the modulation of macrophage functions by these agents. Thus, the long term objectives in this research area are to investigate direct effects of glucocorticoids and other immunopharmacological agents on macrophage functions such as phagocytosis, antigen presentation and tumoricidal capacity. The research proposed in this application is limited in scope to testing the following hypothesis to explain the inhibition of phagocytosis of Saccharomyces cerevisiae in dexamethasone treated cultures of murine resident peritoneal macrophages. The MECHANISM underlying the suppression of yeast ingestion in glucocorticoid treated macrophage cultures is characterized as follows: (1) It is mediated by "PIP", a steroid induced Phagocytosis Inhibitory Protein, which is indistinguishable from lipocortin, a steroid induced phospholipase regulatory protein; (2) It requires active macromolecular metabolism for PIP activity to suppress yeast ingestion; (3) It is activated by achieving and maintaining effective PIP concentrations; (4) It is regulated by effector molecules that modulate phospholipase and protein kinase activities either directly or indirectly; (5) It is common to the mechanisms underlying steroid induced suppression of endocytosis in other model systems; and lastly, (6) It does not interfere with the microbicidal capacity of phagocytes exposed to these steroids. Therefore, the specific aims include (1) isolating and characterizing PIP biochemically for comparison to lipocortin, (2) investigating whether PIP expression requires de novo RNA and protein biosynthesis, (3) correlating PIP concentrations to the magnitude of the inhibitory response, (4) exploring whether PIP activity is blocked or reversed by substances that stimulate lipid enzymes, (5) determining whether PIP Is induced and acts in other endocytosis systems, and (6) ascertaining whether PIP activity is microbicidal. Achieving these specific aims will provide fresh insights into the mechanism by which steroid induced PIP suppresses the very important macrophage function of phagocytosis. This new knowledge may be applied in future studies designed to separate the beneficial anti-inflammatory effects of glucocorticoids from their detrimental immunosuppressive effects by new or novel combined chemotherapeutic-immunotherapeutic regimens.