Role of Prostaglandin E2 on Amoebic Liver Abscess Formation in Hamsters

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Abstract

Entamoeba histolytica can modulate macrophage functions and cytokine production by a prostaglandin E2 (PGE2) mechanism. To study the participation of PGE2 on amoebic liver abscess formation, we tested the effect of the PG synthesis inhibitor indomethacin (INDO) on abscess development in hamsters infected intrahepatically with E. histolytica trophozoites. Male infected animals had higher levels of plasma PGE2 (5.7 ± 0.7 pg/ml pre-infection; 26.0 ± 2.0 pg/ml 7 days postinfection; p < 0.001). INDO prevented this increase, so that infected-treated and control non-infected animals had similar levels of plasma PGE2. INDO reduced liver and abscess weight by 18% and 30% respectively (p < 0.05). Cyclooxygenase (COX) activity determination by thin layer chromatography using (1-14C) arachidonic acid (AA) showed that liver microsomes from infected animals produced more PGE2 than controls. COX activity was considerably inhibited in infected INDO-treated animals. Our data suggest that E. histolytica can stimulate the hepatic production of PGE2 which contributes to pathogenesis of amoebic abscesses through generation and support of the inflammation. The partial effect of INDO treatment suggests that additional factors are involved.

Introduction

Prostaglandins are involved in inflammatory processes. PGE2 is a potent immunomodulatory agent which stimulates the production of TH2-type interleukins (IL) (mainly IL-4 and IL-5), and suppresses the TH1 subset (IL-2 and IFN-γ). This results in inhibition of macrophage activation, a critical event in the development of an adequate immune response against infectious agents1, 2. E. histolytica infections are associated with suppression of cell-mediated immunity, particularly in impaired macrophage effector functions[3]. E. histolytica can modulate the response of macrophages derived from amoebic liver abscess (AMa) by decreasing the production of tumor necrosis factor (TNF) in response to amoebic proteins. Moreover, TNF levels were augmented in AMa pretreated with INDO, suggesting a role for PGE2 in the regulation of TNF production during the pathogenesis of amoebiasis[4]. Additionally, peritoneal macrophages from naive gerbils or AMa produced more PGE2 in response to E. histolytica[5].

Furthermore, E. histolytica suppressed IFN-γ-induced macrophage surface Ia molecule synthesis and IAβ-mRNA expression by a PGE2-dependent mechanism[6]. These data suggest a possible relationship between PGE2 production and suppression of the immune system during the formation of amoebic abscess. We therefore evaluated the effect of INDO treatment in hamsters infected intrahepatically with E. histolytica.

Section snippets

Materials and Methods

Sodium bicarbonate, sodium citrate, trizma base, sucrose, glutathione and citric acid from Sigma Chemicals, USA; ethanol, acetic acid, chloroform, methanol, ethyl acetate and HPLC grade hexane from Baker, USA; Amprep C-18 minicolumns and (1-14C) arachidonic acid (AA) from Amersham International, England; PGE2 standard solution and PGE2 ELISA kit from Boehringer Mannheim Biochem., Germany; autoradiography films X-OMAT and development solutions from Eastman Kodak, USA; silica gel G-60 plates from

Results

Intrahepatic inoculation of 0.5 × 106 trophozoites induced the formation of an abscess, starting at the inoculation site and spreading to the adjacent tissue, following an irregular pattern to invade the rest of the liver (Fig. 1, B). The abscess in INDO- treated animals (10 mg/kg body weight) showed a different pattern with more regular contours and well defined boundaries with the parenchyma (Fig. 1, A). Liver weight increased from 3.5 ± 0.6 g in control animals to 7.2 ± 1.1 g (P < 0.05) in

Discussion

In the present study we have shown that intrahepatic inoculation of trophozoites produces a hepatic abscess concomitant with increased plasma levels of PGE2. Furthermore, pretreatment of the animals with the COX inhibitor INDO reduced the development of the hepatic abscess and prevented the increase of plasma PGE2.

Hepatic abscess formation by E. histolytica occurs because the host defenses can not eliminate the trophozoites. Therefore, the possibility arises that increased plasma levels of PGE2

Acknowledgements

The authors thank Dr. Victor Tsutsumi and Alicia Ramírez-Rosales for generously providing HM1:IMSS strain of E. histolytica and Melody Steinberg and Dr. Partha Pratim Chaudhuri for critically reading the manuscript. We also thank Leonor Zuñiga and Leticia Pérez for their excellent technical assistance. Sánchez-Ramírez, B. was the recipient of a Ph.D. fellowship from the National Council for Science and Technology of México (CONACYT).

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