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Elevated cAMP levels reverse Brucella melitensis-induced lipid peroxidation and stimulate IL-10 transcription in rats
S Erdogan1, S Celik, O Aslantas
1Department of Biochemistry, Faculty of Veterinary Medicine, Mustafa Kemal University, 31034 Antakya, Turkey. serdogan@mku.edu.tr
Abstract:
Brucella species are able to survive and replicate within the phagocytic vacuole of macrophages that induce chronic infection in humans and domestic animals. The activation of oxidative bactericidal activity is one of the defense systems which protect the host from the toxic effects of pathogens. The aim of this study was to evaluate lipid peroxidation, NO production, antioxidative system and inflammation during a period of brucella infection in a rat model; in addition to investigate the role of elevated intracellular cyclic AMP on Brucella-induced events. Brucella significantly induced lipid peroxidation in plasma, liver and spleen by 3-5-fold at 7 days postinfection. NO concentration was significantly elevated in the liver and spleen while unchanged in plasma. Cyclic AMP elevating agent, rolipram, administration (1mg/kg/day i.p., 3 days) gradually suppressed lipid peroxidation and NO formation to the basal level in plasma and spleen whilst only a slight decrease was observed in liver. Brucella considerably decreased SOD activity in the liver and spleen, with rolipram restoring the enzyme activity in liver and activity in spleen being unchanged. Reverse transcriptase PCR analyses showed that Brucella melitensis does not alter TNF-alpha and IFN-gamma transcriptions in liver and spleen. The pathogen did not consistently induce nitric oxide synthase mRNA transcriptions in animals; even in those housed in the same group. IL-10 transcription was induced by rolipram in spleen but not in liver. Our results suggest that activation of the cAMP/PKA pathway suppressed lipid peroxidation and the elevated NO concentrations caused by B. melitensis. Moreover, rolipram induced anti-inflammatory cytokine IL-10 transcription and SOD activity, albeit in a tissue dependent manner.
Insights
Elevating cyclic AMP with rolipram suppressed Brucella-induced oxidative stress and inflammation in rats. This pathway activation reduced lipid peroxidation and nitric oxide, while boosting antioxidant enzymes and IL-10, indicating a potential therapeutic strategy.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Brucella species cause chronic infections by surviving within macrophages.
- Oxidative bactericidal activity is a key host defense mechanism against pathogens.
- Understanding host-pathogen interactions and host defense modulation is crucial for managing Brucella infections.
Purpose of the Study:
- To investigate oxidative stress markers (lipid peroxidation, NO production) and the antioxidative system during Brucella infection in rats.
- To evaluate the role of elevated intracellular cyclic AMP (cAMP) in modulating Brucella-induced host responses.
- To assess the impact of rolipram, a cAMP elevating agent, on inflammation and specific cytokine transcription.
Main Methods:
- Establishment of a rat model of Brucella infection.
- Measurement of lipid peroxidation and nitric oxide (NO) concentrations in plasma, liver, and spleen.
- Administration of rolipram to modulate intracellular cAMP levels.
- Assessment of superoxide dismutase (SOD) activity and transcription of TNF-alpha, IFN-gamma, inducible nitric oxide synthase (iNOS), and IL-10 using RT-PCR.
Main Results:
- Brucella infection significantly increased lipid peroxidation and NO levels in liver and spleen, while decreasing SOD activity.
- Rolipram administration suppressed lipid peroxidation and NO formation, restoring SOD activity in the liver.
- Brucella did not consistently alter TNF-alpha, IFN-gamma, or iNOS transcription, but rolipram induced IL-10 transcription in the spleen.
Conclusions:
- Activation of the cAMP/PKA pathway effectively suppresses Brucella-induced oxidative stress and elevated NO levels.
- Rolipram demonstrates anti-inflammatory effects by inducing IL-10 transcription and enhancing SOD activity in a tissue-specific manner.
- Modulating intracellular cAMP represents a potential therapeutic strategy against Brucella infections.