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Pentoxifylline Inhibits Endotoxin-Induced NF-kappa B Activation and Associated Production of Proinflammatory Cytokines

Address correspondence to Jianguo Xu, M.D.; Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, People’s Republic of China; tel 86 25 8480 6839; fax 86 25 8480 6839; e-mail: jiqing73{at}sina.com.

The effects of graded doses of pentoxifylline (PTX) on endotoxin-induced production of inflammatory cytokines and activation of nuclear factor kappa B (NF-B) 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-B activation in intestine was investigated by electrophoretic mobility shift assay (EMSA). Tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6), and interleukin-10 (IL-10) levels were measured in intestine by enzyme-linked immunosorbance assays (ELISA). Intestinal TNF-, IL-6, and IL-10 mRNA expression were studied by the reverse-transcription polymerase chain reaction (RT-PCR). The measurements of NF- B, TNF-, 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-, IL-6, and IL-10 and enhanced NF-B activation in rat intestine. At all dosages, PTX reduced the activation of NF-B and the production of TNF- and IL-6, but enhanced the release of IL-10. These effects were greatest at dosages of 50 mg/kg for TNF- and IL-6, and 25 mg/kg for IL-10. In conclusion, PTX suppressed the production of proinflammatory cytokines such as TNF- 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-B activation, but not by induction of IL-10.

Keywords: pentoxifylline, NF-B, TNF-, interleukin-6, interleukin-10

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