Association of Tumor Necrosis Factor, Interleukin-6 and Cyclooxygenase Pathway with Lipopolysaccharide-Induced Intussusception

Abstract

Introduction: Many factors and mechanisms have been proposed as causes for intussusception (IN); however, the etiology remains unclear. Inflammatory mediators such as tumor necrosis factor (TNF) and interleukin-6 (IL-6), which are elevated during infectious diseases, can significantly affect gastrointestinal motility. Motility changes caused by these agents might contribute to the development of IN. The aim of this experimental study was to determine the preventive effects of indomethacin on lipopolysaccharide (LPS)-induced IN in mice and to investigate the role of TNF and IL-6 on intussusception. Materials and Methods: Seventy-eight mice were divided into five groups. In the Control group (n = 6), no procedure was done. In the Sham group (n = 6), 1 ml saline, in the Indomethacin group (n = 6), 10 mg/kg of indomethacin, in the LPS group (n = 30), 12 mg/kg of LPS was administered intraperitoneally (IP). In the Treatment group (n = 30), 10 mg/kg of indomethacin was administered IP following 12 mg/kg of LPS. All animals were laparotomized 6 hours following IP injections. The existence of IN was noted and blood specimens were obtained. TNFα and IL-6 plasma level measurements were performed by standard ELISA for mice. The results were compared using the Mann-Whitney U test and one-way ANOVA test. A value of p < 0.05 was considered significant. Results: Five mice (1 in the control, 2 in the LPS, 2 in the Treatment group) were excluded from the study. IN was observed in 6 (20 %) mice in the LPS group, whereas it was not found in any mice in the Treatment group. Mean TNFα and IL-6 levels were statistically higher in the LPS group (394.72 ± 403.79; 195.18 ± 218.37 pg/ml, respectively) compared to all other groups, including the Treatment group (p < 0.05 for each comparison). Within the LPS group of mice, the levels were higher in animals with IN compared to the mice without IN. Conclusion: Increased TNFα and IL-6 levels induced by LPS correlated well with the occurrence of IN, and a decrease in these levels via cyclooxygenase (COX) inhibition by indomethacin prevented IN from forming in this experimental model.

Key words

tumor necrosis factor (TNF) - interleukin - indomethacin - intussusception

References

• 1 Bour A M, Westendorp R G, Laterveer J C, Bollen E L, Remarque E J. Interaction of indomethacin with cytokine production in whole blood. Potential mechanism for a brain- protective effect.  Exp Gerontol. 2000;  35 1017-1024
• 2 Ceregrzyn M, Kamata T, Yajima T, Kuwahara A. Biphasic alterations in gastrointestinal transit following endotoxaemia in mice.  Neurogastroenterol Motil. 2001;  13 605-613
• 3 Cullen J J, Doty R C, Ephgrave K S, Hinkhouse M M, Broadhurst I C. Changes in intestinal transit and absorption during endotoxemia are dose dependent.  J Surg Res. 1999;  81 81-86
• 4 Ein S H, Daneman A. Intussusception. Ziegler MM, Azizkhan RG, Weber TR Operative Pediatric Surgery. New York; McGraw-Hill 2003: 647-655
• 5 Fallat M E. Intussusception. Ashcraft KW, Murphy JP, Sharp R et al. Pediatric Surgery. Philadelphia; W.B. Saunders 2000: 518-526
• 6 Frantzides C T, Mathias C, Ludwig K A, Edmiston C E. Small bowel myoelectric activity in peritonitis.  Am J Surg. 1993;  165 681-685
• 7 Guerrero-Lindner E, Castro M, Munoz J M, Arruebo M P, Murillo M D, Bueno L, Plaza M A. Central tumour necrosis factor-alpha mediates the early gastrointestinal motor disturbances induced by lipopolysaccharide in sheep.  Neurogastroenterol Motil. 2003;  15 307-316
• 8 Hau T. Bacteria, toxins, and the peritoneum.  World J Surg. 1990;  14 167-175
• 9 Hellström P M, Al-Saffar A, Ljung T, Theodorsson E. Endotoxin actions on myoelectric activity, transit and neuropeptides in the gut role of nitric oxide.  Dig Dis Sci. 1997;  42 1640-1651
• 10 Jansky L, Vybiral S, Pospisilova D, Roth J, Dornand J, Zeisberger E, Kaminkova J. Production of systemic and hypothalamic cytokines during the early phase of endotoxin fever.  Neuroendocrinology. 1995;  62 55-61
• 11 Justice F, Carlin J, Bines J. Changing epidemiology of intussusception in Australia.  J Paediatr Child Health. 2005;  41 475-478
• 12 King J N, Gerring E L. Antagonism of endotoxin-induced disruption of equine gastrointestinal motility with the platelet-activating factor antagonist WEB 2086.  J Vet Pharmacol Ther. 1990;  13 333-339
• 13 Konturek P C, Brzozowski T, Konturek S J, Kwiecien S, Dembinski A, Hahn E G. Influence of bacterial lipopolysaccharide on healing of chronic experimental ulcer in rat.  Scand J Gastroenterol. 2001;  36 1239-1247
• 14 Lin Z, Cohen P, Nissan A, Allweis T M, Freund H R, Hanani M. Bacterial wall lipopolysaccharide as a cause of intussusception in mice.  J Pediatr Gastroenterol Nutr. 1998;  27 301-305
• 15 Masne A L, Lortat-Jacob S, Sayegh N, Sannier N, Brunelle F, Cheron G. Intussusception in infants and children: feasibility of ambulatory management.  Eur J Pediatr. 1999;  158 707-710
• 16 Matsuda H, Li Y, Yoshikawa M. Roles of endogenous prostaglandins and nitric oxide in inhibitions of gastric emptying and accelerations of gastrointestinal transit by escins Ia, Ib, II a and II b in mice.  Life Sci. 2000;  66 PL41-PL46
• 17 Million M, Fioramonti J, Zajac J M, Bucano L. Effects of neuropeptide FF on intestinal motility and temperature changes induced by endotoxin and platelet-activating factor.  Eur J Pharmacol. 1997;  334 67-73
• 18 Nissan A, Zhang J M, Lin Z, Haskel Y, Freund H R, Hanani M. The contribution of inflammatory mediators and nitric oxide to lipopolysaccharide-induced intussusception in mice.  J Surg Res. 1997;  69 205-207
• 19 Pons L, Droy-Lefaix M T, Braquet P, Bueno L. Involvement of platelet-activating factor (PAF) in endotoxin-induced intestinal motor disturbances in rats.  Life Sci. 1989;  45 533-541
• 20 Rees D D, Celleck S, Palmer R MJ, Moncada S. Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock.  Biochem Biophys Res Commun. 1990;  173 541-547
• 21 Robinson C G, Hernanz-Schulman M, Zhu Y, Griffin M R, Gruber W, Edwards K M. Evaluation of anatomic changes in young children with natural rotavirus infection: is intussusception biologically plausible?.  J Infect Dis. 2004;  189 1382-1387
• 22 Salvemini D, Misko T P, Masferrer J L, Seibert K, Currie M G, Needleman P. Nitric oxide activates cyclooxygenase enzymes.  Proc Natl Acad Sci USA. 1993;  90 7240-7244
• 23 Spiro D M, Schmidt J M, Arnold D H, Cartner S C, Yagmurlu A. Antibiotic-induced mesenteric adenopathy in an intussusception mouse model: a randomized, controlled trial.  J Pediatr Gastroenterol Nutr. 2005;  41 39-43
• 24 Willetts I E, Kite P, Barclay G R, Banks R E, Rumley A, Allgar V, Stringer M D. Endotoxin, cytokines and lipid peroxides in children with intussusceptions.  Br J Surg. 2001;  88 878-883
• 25 Young D G. Intussusception. O'Neil JA, Rowe MI, Grosfeld JL et al. Pediatric Surgery. St. Louis; Mosby Year Book 1998: 1185-1198