Molecular Endocrinology Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina, USA.
J Clin Invest. 2019 Mar 1;129(3):1345-1358. doi: 10.1172/JCI123233. Epub 2019 Feb 18.
In the stomach, chronic inflammation causes metaplasia and creates a favorable environment for the evolution of gastric cancer. Glucocorticoids are steroid hormones that repress proinflammatory stimuli, but their role in the stomach is unknown. In this study, we show that endogenous glucocorticoids are required to maintain gastric homeostasis. Removal of circulating glucocorticoids in mice by adrenalectomy resulted in the rapid onset of spontaneous gastric inflammation, oxyntic atrophy, and spasmolytic polypeptide-expressing metaplasia (SPEM), a putative precursor of gastric cancer. SPEM and oxyntic atrophy occurred independently of lymphocytes. However, depletion of monocytes and macrophages by clodronate treatment or inhibition of gastric monocyte infiltration using the Cx3cr1 knockout mouse model prevented SPEM development. Our results highlight the requirement for endogenous glucocorticoid signaling within the stomach to prevent spontaneous gastric inflammation and metaplasia, and suggest that glucocorticoid deficiency may lead to gastric cancer development.
在胃部，慢性炎症会导致化生，并为胃癌的发展创造有利环境。糖皮质激素是一种抑制促炎刺激的甾体激素，但它们在胃中的作用尚不清楚。在这项研究中，我们表明内源性糖皮质激素是维持胃稳态所必需的。通过肾上腺切除术去除小鼠循环中的糖皮质激素会导致自发性胃炎症、贲门萎缩和舒血管肠肽表达的化生（SPEM）迅速发生，SPEM 是胃癌的一个潜在前体。SPEM 和贲门萎缩发生与淋巴细胞无关。然而，用氯膦酸盐处理耗尽单核细胞和巨噬细胞，或使用 Cx3cr1 基因敲除小鼠模型抑制胃单核细胞浸润，可防止 SPEM 的发展。我们的结果强调了内源性糖皮质激素信号在胃内的必要性，以防止自发性胃炎症和化生，并表明糖皮质激素缺乏可能导致胃癌的发展。
