COX-1 and COX-2 tissue expression: implications and predictions.
COX-1 and COX-2 tissue expression: implications and predictions.
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发表时间：
1997-07
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通讯作者：
L. Crofford
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作者：
L. Crofford
有人提出，环氧合酶 (COX)-1 和 COX-2 具有不同的生理功能，很大程度上是因为它们的组织表达和调节存在显着差异。 COX-1表现出“看家”基因的特征，并且在几乎所有组织中组成型表达。 COX-1 似乎负责前列腺素 (PG) 的产生，前列腺素对体内平衡功能很重要，例如维持胃粘膜的完整性、介导正常的血小板功能和调节肾血流。与此形成鲜明对比的是，COX-2 是“立即早期”基因的产物，该基因可快速诱导并受到严格调控。在基础条件下，COX-2的表达受到高度限制；然而，COX-2 在炎症过程中显着上调。例如，类风湿性关节炎 (RA) 患者的滑膜组织中 COX-2 的表达水平升高。在炎症性关节炎的动物模型中，COX-2 与 PG 产生和临床炎症同时增加。体外实验表明，在许多细胞类型（包括滑膜细胞、内皮细胞、软骨细胞、成骨细胞和单核细胞/巨噬细胞）中，用促炎细胞因子（例如白细胞介素 1 (IL-1) 和肿瘤坏死因子-α (TNF-α)）刺激后，COX-2 表达增加。 COX-2 的另一个显着特征是响应糖皮质激素而表达减少。 COX-2 在某些类型的人类癌症中也会增加，特别是结肠癌。 COX-2 过度表达与致瘤潜力之间的关联机制可能包括对细胞凋亡或程序性细胞死亡的抵抗。 COX-2 表达上调无疑在以局部 PG 产生增加为特征的病理过程中发挥作用。根据目前关于 COX-1 和 COX-2 差异组织表达的信息，人们可以预测，COX-2 的高选择性抑制剂将提供有效的抗炎活性，同时显着降低毒性。
It has been proposed that cyclooxygenase (COX)-1 and COX-2 subserve different physiologic functions largely because of the striking differences in their tissue expression and regulation. COX-1 displays the characteristics of a "housekeeping" gene and is constitutively expressed in almost all tissues. COX-1 appears to be responsible for the production of prostaglandins (PG) that are important for homeostatic functions, such as maintaining the integrity of the gastric mucosa, mediating normal platelet function, and regulating renal blood flow. In sharp contrast, COX-2 is the product of an "immediate-early" gene that is rapidly inducible and tightly regulated. Under basal conditions, COX-2 expression is highly restricted; however, COX-2 is dramatically upregulated during inflammation. For example, synovial tissues in patients with rheumatoid arthritis (RA) express increased levels of COX-2. In animal models of inflammatory arthritis, COX-2 increases in parallel with PG production and clinical inflammation. In vitro experiments have revealed increased COX-2 expression after stimulation with proinflammatory cytokines, such as interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), in many cell types, including synoviocytes, endothelial cells, chondrocytes, osteoblasts, and monocytes/macrophages. Another distinguishing characteristic of COX-2 is decreased expression in response to glucocorticoids. COX-2 is also increased in some types of human cancers, particularly colon cancer. Mechanisms underlying the association between COX-2 overexpression and tumorigenic potential may include resistance to apoptosis, or programmed cell death. Upregulated COX-2 expression undoubtedly plays a role in pathologic processes characterized by increased local PG production. One would predict, based on current information regarding the differential tissue expression of COX-1 and COX-2, that highly selective inhibitors of COX-2 will provide effective antiinflammatory activity with marked reduction in toxicity.