MECHNSMS OF STEROID INHIBITION OF MICROBIAL PHAGOCYTOSIS

糖皮质激素是一种有效的免疫抑制剂。这个 这些药物发挥有害作用的机制 是很复杂的。与我们对类固醇作用于 淋巴细胞的功能，对它的调节知之甚少 这些药物对巨噬细胞功能的影响。因此，从长远来看， 这一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药物的作用 巨噬细胞的吞噬、抗原提呈等功能 和杀瘤能力。这项研究中提出的 应用范围仅限于检验以下假设 酵母菌吞噬抑制作用的解释 地塞米松处理小鼠常住鼠培养物中的酿酒酵母 腹膜巨噬细胞。其背后的机制是 糖皮质激素治疗对酵母摄取的抑制作用 巨噬细胞培养的特点如下：(1) 由“PIP”介导的类固醇诱导的吞噬抑制作用 蛋白质，与类固醇脂皮质分不开 诱导磷脂酶调节蛋白；(2)需要活性 PIP抑制酵母菌活性的大分子代谢 摄取；(3)通过实现和保持激活它 有效PIP浓度；(4)受效应器调节 调节磷脂酶和蛋白激酶的分子 直接或间接的活动；(5) 类固醇抑制细胞吞噬作用的机制 在其他模型系统中；最后，(6)它不干扰 暴露在这些类固醇中的吞噬细胞的杀菌能力。 因此，具体目标包括(1)隔离和 PIP的生化表征以与脂皮质相比较，(2) 研究PIP表达是否需要从头RNA和 蛋白质生物合成，(3)PIP浓度与 抑制性反应的大小，(4)探讨PIP是否 活性被刺激脂肪的物质阻断或逆转 酶，(5)确定PIP是否被诱导并作用于其他 内吞系统，以及(6)确定PIP活性是否 杀微生物剂。实现这些具体目标将提供新的 类固醇诱导PIP机制的研究进展 抑制非常重要的巨噬细胞功能 吞噬作用。这一新知识将来可能会被应用。 旨在将有益的抗炎药物分离的研究 糖皮质激素对人体健康的影响 新的或新的组合的免疫抑制作用 化疗-免疫治疗方案。

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.