Effective immunomodulatory treatment of Escherichia coli experimental sepsis with thalidomide

Thalidomide, an agent which inhibits biosynthesis of tumor necrosis factor alpha (TNF-alpha) and which is used to treat a variety of chronic inflammatory conditions, was investigated as therapy for experimental sepsis. Sepsis was induced by intraperitoneal injection of 10(7) CFU of Escherichia coli per kg of body weight to 80 Wistar rats divided into four groups. Group A consisted of 24 control animals that did not receive any pretreatment, group B consisted of 18 vehicle-treated control animals pretreated with seed oil, group C consisted of 30 rats administered thalidomide diluted in seed oil at a dose of 50 mg/kg 30 min before bacterial challenge, and group D consisted of eight animals that were not challenged with E. coli but that were used for white blood cell count determination. Sepsis was determined by measurement of vital signs before and 6 h after bacterial challenge. After 6 h the animals were killed and blood was sampled for culture; white blood cell count determination; and determination of endotoxin (lipopolysaccharide), TNF-alpha, interleukin-1beta (IL-1beta), and IL-6 levels. The levels of these cytokines were also estimated in the supernatants of human monocytes pretreated with thalidomide after exposure to the isolate. Sepsis developed in all vehicle-treated control animals and controls by 6 h after bacterial challenge but in only 10 animals (33.3%) pretreated with thalidomide (P < 0.0001). Six hours after bacterial challenge all animals had similar levels of endotoxemia, IL-10, and IL-6. The mean white blood cell count for groups A, B, and C were 5,631.1, 2,638.9, and 8,169.3 cells/mu l, respectively (P value between groups, <0.0001); the TNF-alpha levels were 77.3, 107.2, and 26.1 pg/ml, respectively (P values between groups, <0.0001). Pretreatment of human monocytes with thalidomide prevented the secretion of TNF-alpha and IL-1 beta but not that of IL-6. It is concluded that thalidomide exerts a considerable anti-inflammatory effect by preventing evolution to sepsis and by decreasing the level of production of TNF-alpha and therefore deserves to be further evaluated in research for the therapy of sepsis.