Takahashi S, Kobayashi N, Okabe S
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
J Pharmacol Exp Ther. 1999 Nov;291(2):634-41.
We investigated the role of endogenous interleukin (IL)-1 in the mRNA expression of cyclooxygenase (COX)-1, COX-2, inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant (CINC)-1, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor (TGF)-beta1 in acetic acid-induced gastric ulcers in rats. IL-1beta mRNA was not detected in the normal or intact mucosa of ulcerated stomachs, but its expression was induced in the ulcerated tissue. IL-1beta immunoreactivity was observed in macrophages/monocytes and fibroblasts in the ulcer base. COX-2, iNOS, and CINC-1 mRNAs were expressed by ulceration. EGF, bFGF, HGF, and TGF-beta1 mRNA expression was detected in the normal mucosa, and their levels were significantly elevated by ulceration. In contrast, COX-1 mRNA level did not differ between the normal and ulcerated tissues. In a culture of isolated ulcer bases, block of IL-1 with IL-1 receptor antagonist (IL-1RA) dose-dependently and significantly reduced the mRNA levels of COX-2, iNOS, CINC-1, HGF, and bFGF. In contrast, COX-1, EGF, and TGF-beta1 mRNA expression was not affected by IL-1RA. IL-1RA dose-dependently reduced prostaglandin E(2) production, total and iNOS activities, neutrophil chemotactic activity, and growth-promoting activity toward gastric epithelial cells in the ulcer base. Finally, the administration of IL-1RA caused a significant impairment of ulcer healing. These results indicate that IL-1, expressed in macrophages/monocytes and fibroblasts in the ulcer base, might up-regulate the mRNA expression of COX-2, iNOS, CINC-1, HGF, and bFGF, thereby contributing to gastric ulcer healing in rats.
我们研究了内源性白细胞介素（IL）-1在大鼠乙酸诱导的胃溃疡中对环氧化酶（COX）-1、COX-2、诱导型一氧化氮合酶（iNOS）、细胞因子诱导的中性粒细胞趋化因子（CINC）-1、表皮生长因子（EGF）、碱性成纤维细胞生长因子（bFGF）、肝细胞生长因子（HGF）和转化生长因子（TGF）-β1 mRNA表达的作用。在正常或未受损的溃疡胃黏膜中未检测到IL-1β mRNA，但其在溃疡组织中表达被诱导。在溃疡底部的巨噬细胞/单核细胞和成纤维细胞中观察到IL-1β免疫反应性。COX-2、iNOS和CINC-1 mRNA因溃疡而表达。在正常黏膜中检测到EGF、bFGF、HGF和TGF-β1 mRNA表达，且其水平因溃疡而显著升高。相比之下，正常组织和溃疡组织之间COX-1 mRNA水平没有差异。在分离的溃疡底部培养物中，用IL-1受体拮抗剂（IL-1RA）阻断IL-1可剂量依赖性且显著降低COX-2、iNOS、CINC-1、HGF和bFGF的mRNA水平。相比之下，COX-1、EGF和TGF-β1 mRNA表达不受IL-1RA影响。IL-1RA剂量依赖性降低溃疡底部前列腺素E2的产生、总一氧化氮合酶和诱导型一氧化氮合酶活性、中性粒细胞趋化活性以及对胃上皮细胞的促生长活性。最后，给予IL-1RA导致溃疡愈合显著受损。这些结果表明，在溃疡底部的巨噬细胞/单核细胞和成纤维细胞中表达的IL-1可能上调COX-2、iNOS、CINC-1、HGF和bFGF的mRNA表达，从而促进大鼠胃溃疡的愈合。
