Potencial imunomodulatório da 1,3,7 trimetilxantina em modelos de infecção experimental por Listeria monocytogenes

Abstract

Bacterial diseases are one of the main causes of mortality in the world and there is a great concern in health services when it comes to antibiotic resistant strains, requiring science to always investigate new treatment alternatives. Studies with caffeine (1,3,7 trimethylxanthine) show its influence on physiological processes, including modulation of the immune system, presenting an anti-inflammatory potential. In this study, the hypothesis that caffeine would be able to influence the inflammatory response derived from infectious processes was evaluated using a virulent strain of Listeria monocytogenes as a bacterial infection model. This species causes listeriosis, a disease transmitted through contaminated food that affects humans and animals. Tests were carried out to determine whether caffeine would have an inhibitory effect on the growth of L. monocytogenes in vitro. Peritoneal macrophage cultures (pMΦ) obtained from Swiss mice were subjected to infection with the bacteria and treatment with caffeine (0.05, 0.5 and 5 μg/mL), using two schemes: a) treatment with caffeine followed by infection; b) infection followed by caffeine treatment. Intracellular bacterial quantification and pMΦ viability were measured at the end of the experiments. Subsequently, in vivo tests were performed to determine the anti-inflammatory potential of caffeine. In this case, the animals in the experimental group were intraperitoneally infected with L. monocytogenes (0.2 mL; 1 x 107 cells/mL) and, after 30 minutes, they were treated with caffeine, intravenously, at concentrations of 0 .05; 0.5 or 5 mg/kg. As controls, infected animals and administered with phosphate saline (PBS) or with the anti-inflammatory dexamethasone (DEXA) were used. After 6 hours the animals were sacrificed, the amount of leukocytes in the peritoneal fluid and blood determined, and the bacteria were quantified in different tissues and organs. A fragment of the spleen was dissected for analysis of gene expression of the cytokines TNF-α, IL-1β, IL-6, IL-10 and the enzyme Nitric Oxide Synthase inducible (iNOS). The results showed that caffeine does not have a direct antimicrobial action against L. monocytogenes, but it was able to increase the viability of infected macrophages, although there is no greater elimination of the bacteria inside the pMΦ. In in vivo tests, the administration of caffeine produced an anti-inflammatory action, significantly reducing the recruitment of leukocytes to the peritoneal cavity and the amount of circulating leukocytes in the blood. When compared to the control group, the gene expression of the inflammatory cytokines IL-1β and IL-6 was decreased and that of the anti-inflammatory cytokine IL-10 was increased. The expression of the iNOS enzyme was also decreased in the groups treated with caffeine, when compared to the PBS infected group. The data presented here point to the potential of using caffeine as an anti-inflammatory in preventing severe inflammatory processes derived from bacterial infections.