Inhibition of TNF-α production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

Abstract

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)-α and interleukin (IL)-1β 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-α synthesis. The goal of our study was to investigate whether inhibition of TNF-α 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 anti-catabolic 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-α and IL-1β and their hepatic expression (P<0.01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-α (- 98% at 90 min; P< 0.001 vs LPS alone) and to a lesser extent in serum IL-1β ( - 44% at 3 h; not significant vs LPS alone. Despite its dramatic inhibitory effect on TNF-α 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-α, in particular IL-1β 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.