Colson A, Willems B, Thissen J-P
Unité de Diabétologie et Nutrition, Université Catholique de Louvain, B-1200 Bruxelles, Belgium.
J Endocrinol. 2003 Jul;178(1):101-9. doi: 10.1677/joe.0.1780101.
Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta inhibit the GH-stimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-alpha synthesis. The goal of our study was to investigate whether inhibition of TNF-alpha production by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I (-45% at 12 h; P<0.01 vs time 0) and its liver mRNA (-67% at 12 h; P<0.01 vs time 0) while it induced circulating TNF-alpha and IL-1beta and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-alpha (-98% at 90 min; P<0.001 vs LPS alone) and to a lesser extent in serum IL-1beta (-44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-alpha induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-alpha, in particular IL-1beta or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.
脓毒症和注射内毒素（脂多糖，LPS）会引发生长激素（GH）抵抗状态，导致循环胰岛素样生长因子（IGF）-I水平降低。由于促炎细胞因子肿瘤坏死因子（TNF）-α和白细胞介素（IL）-1β在体外可抑制GH刺激的IGF-I表达，因此有人推测这两种细胞因子可能在LPS导致的循环IGF-I水平降低中起重要作用。己酮可可碱是一种常用于治疗外周动脉循环障碍的甲基黄嘌呤，据报道可抑制TNF-α的合成。我们研究的目的是调查己酮可可碱对TNF-α产生的抑制作用是否能预防LPS注射所致的IGF-I降低和GH抵抗。因为先前的研究表明己酮可可碱可减少脓毒症诱导的肌肉分解代谢，我们还评估了己酮可可碱是否能通过防止循环IGF-I降低来发挥其抗分解代谢作用。给大鼠注射LPS可降低血清IGF-I（12小时时降低45%；与0小时相比P<0.01）及其肝脏mRNA水平（12小时时降低67%；与0小时相比P<0.01），同时诱导循环TNF-α和IL-1β及其肝脏表达（P<0.01）。用己酮可可碱对LPS处理的动物进行预处理可消除LPS诱导的血清TNF-α升高（90分钟时降低98%；与单独注射LPS相比P<0.001），对血清IL-1β的降低作用较小（3小时时降低44%；与单独注射LPS相比无统计学意义）。然而，尽管己酮可可碱对TNF-α诱导有显著抑制作用，但它未能抑制LPS诱导的大鼠IGF-I降低和GH抵抗。这些结果表明，除TNF-α外的其他介质（特别是IL-1β或IL-6）可能导致LPS诱导的GH抵抗。它们还表明，己酮可可碱的抗分解代谢作用并非由于预防循环IGF-I的下降。
