Pentoxifylline inhibits endotoxin-induced NF-kappa B activation and associated production of proinflammatory cytokines

Abstract

The effects of graded doses of pentoxifylline (PTX) on endotoxin-induced production of inflammatory cytokines and activation of nuclear factor kappa B (NF-kappaB) were studied in vivo in rat intestine. Sepsis was induced in rats by ip injection of lipopolysaccharide (LPS, 5 mg/kg). PTX was injected via the tail vein at dosages of 6.25, 12.5, 25, 50, or 100 mg/kg at 1 min after LPS challenge. NF-kappaB activation in intestine was investigated by electrophoretic mobility shift assay (EMSA). Tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were measured in intestine by enzyme-linked immunosorbance assays (ELISA). Intestinal TNF-alpha, IL-6, and IL-10 mRNA expression were studied by the reverse-transcription polymerase chain reaction (RT-PCR). The measurements of NF-kappaB, TNF-alpha, IL-6, and IL-10 were performed, respectively, at 1, 4, 4, and 1 hr after endotoxin injection. The results showed that LPS elevated the production of TNF-alpha, IL-6, and IL-10 and enhanced NF-kappaB activation in rat intestine. At all dosages, PTX reduced the activation of NF-kappaB and the production of TNF-alpha and IL-6, but enhanced the release of IL-10. These effects were greatest at dosages of 50 mg/kg for TNF-alpha and IL-6, and 25 mg/kg for IL-10. In conclusion, PTX suppressed the production of proinflammatory cytokines such as TNF-alpha and IL-6 in rat intestine, and enhanced the endotoxin-induced production of IL-10. The suppressive effect of proinflammatory cytokines may act by inhibiting NF-kappaB activation, but not by induction of IL-10.