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Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen.

ABSTRACT: This study was designed to investigate whether the pattern of hypothalamic and splenic cytokine expression induced by peripheral administration of a bacterial lipopolysaccharide (LPS) is affected by prior exposure to LPS derived from another bacterial strain. Injection of LPS from Salmonella enteritidis (LPS(2)) alone resulted in increased hypothalamic gene expression of IL-1beta, IL-6, TNFalpha, IL-1ra and IL-10. However, pre-exposure to LPS derived from Escherichia coli (LPS(1)) 3 weeks before, significantly attenuated hypothalamic IL-1ra, IL-6 and IL-10 expression. IL-1beta expression also tended to be lower. This pattern contrasted with the robust cytokine expression in the spleen of LPS(2)-treated rats previously exposed to LPS(1), since pre-treatment with endotoxin resulted in a significantly greater response of IL-1beta and IL-1ra to LPS(2). Expression of TNFalpha and IL-10 also tended to be higher. Pre-treatment with LPS(1) did not significantly affect the marked increase in corticosterone and adrenaline blood levels induced by LPS(2). Thus, while endotoxin pre-exposure seemed not to induce a "tolerant" state in the periphery as judged by the immune and endocrine parameters evaluated upon re-stimulation, expression of four of the six cytokines measured was decreased in the hypothalamus. This is the first demonstration that endotoxin priming can differentially affect cytokine expression in the central nervous system and peripheral tissues when a host is confronted with a second, acute, pro-inflammatory stimulus. These results may provide new evidence for the involvement of cytokine pathways in the central nervous system in modulating peripheral inflammation and mediating cognitive and behavioural alterations during inflammatory diseases.

SUBMITTER: del Rey A

PROVIDER: S-EPMC2715886 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen.

del Rey Adriana A Randolf Anke A Wildmann Johannes J Besedovsky Hugo O HO Jessop David S DS

Brain, behavior, and immunity 20090228 6

This study was designed to investigate whether the pattern of hypothalamic and splenic cytokine expression induced by peripheral administration of a bacterial lipopolysaccharide (LPS) is affected by prior exposure to LPS derived from another bacterial strain. Injection of LPS from Salmonella enteritidis (LPS(2)) alone resulted in increased hypothalamic gene expression of IL-1beta, IL-6, TNFalpha, IL-1ra and IL-10. However, pre-exposure to LPS derived from Escherichia coli (LPS(1)) 3 weeks before ...[more]

PMID: 19254758

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Project description:PURPOSE: The inwardly rectifying potassium channel protein Kir4.1 and the water channel protein aquaporin-4 (AQP4) have been suggested to play essential roles in the potassium and water homeostasis of the retina. In this study, we investigated the expression of Kir4.1 and AQP4 in the retina during endotoxin-induced uveitis (EIU) in rats. METHODS: EIU was induced in male Wistar rats by intravitreal injection of lipopolysaccharide (LPS). The severity of the EIU was evaluated by clinical and histopathological examination. The expression of Kir4.1 and AQP4 in the retina was detected by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemical staining. RESULTS: In the animal model of EIU, the clinical changes correlated well with the histopathological findings. The inflammation peaked at 24 h and resolved by seven day. After an intravitreal LPS injection, the expression of Kir4.1 in the retina showed a significant decline at both the protein and mRNA levels. In the early stages of EIU, the expression of Kir4.1 mRNA decreased sharply, reaching a minimum at 12 h (31%, p<0.001). It then increased gradually and had partially recovered 14 days after LPS injection (92%, p>0.05). The expression of Kir4.1 protein decreased significantly, reaching a minimum at three days after the LPS injection (43%, p<0.001). Thereafter, it increased slightly but was maintained at a low level until 14 days after LPS injection (64%, p<0.001). In contrast, the expression of AQP4 mRNA remained almost unchanged after LPS treatment (p>0.05). The expression of AQP4 protein was only slightly reduced at one day (82%, p>0.05) after LPS injection and then increased gradually and had nearly recovered to the basal level at 14 days after LPS injection. CONCLUSIONS: EIU differently alters the expression of Kir4.1 and AQP4 in the retina. The differential expression of Kir4.1 and AQP4 during EIU implies a disturbance of water and potassium transport in the retina, which may contribute to the retinal edema during ocular inflammation.

Project description:Sleep disordered breathing (SDB) affects 3-5% of the pediatric population, including neonates who are highly susceptible due to an underdeveloped ventilatory control system, and REM-dominated sleep. Although pediatric SDB is associated with poor cognitive outcomes, very little research has focused on models of pediatric SDB, particularly in neonates. In adults and neonates, intermittent hypoxia (IH), a hallmark of SDB, recapitulates multiple physiological aspects of severe SDB, including neuronal apoptosis, sex-specific cognitive deficits, and neuroinflammation. Microglia, resident CNS immune cells, are important mediators of neurodevelopment and neuroinflammation, but to date, no studies have examined the molecular properties of microglia in the context of neonatal IH. Here, we tested the hypothesis that neonatal IH will enhance microglial inflammation and sex-specifically lead to long-term changes in working memory. To test this hypothesis, we exposed post-natal day (P1) neonates with dams to an established adult model of pathological IH consisting of 2 min cycles of 10.5% O2 followed by 21% O2, 8 h/day for 8 days. We then challenged the offspring with bacterial lipopolysaccharide (LPS) at P9 or at 6-8 weeks of age and immunomagnetically isolated microglia for gene expression analyses and RNA-sequencing. We also characterized neonatal CNS myeloid cell populations by flow cytometry analyses. Lastly, we examined working memory performance using a Y-maze in the young adults. Contrary to our hypothesis, we found that neonatal IH acutely augmented basal levels of microglial anti-inflammatory cytokines, attenuated microglial responses to LPS, and sex-specifically altered CNS myeloid populations. We identified multiple sex differences in basal neonatal microglial expression of genes related to chemotaxis, cognition, and aging. Lastly, we found that basal, but not LPS-induced, anti-inflammatory cytokines were augmented sex-specifically in the young adults, and that there was a significant interaction between sex and IH on basal working memory. Our results support the idea that neonates may be able to adapt to IH exposures that are pathological in adults. Further, they suggest that male and female microglial responses to IH are sex-specific, and that these sex differences in basal microglial gene expression may contribute to sexual dimorphisms in vulnerability to IH-induced cognitive disruption.

Project description:UNLABELLED:Previous studies demonstrated that targeted deletion of the Ron receptor tyrosine kinase (TK) domain in mice leads to marked hepatocyte protection in a well-characterized model of lipopolysaccharide (LPS)-induced acute liver failure in D-galactosamine (GalN)-sensitized mice. Hepatocyte protection in TK-/- mice was observed despite paradoxically elevated serum levels of tumor necrosis factor alpha (TNF-?). To understand the role of Ron in the liver, purified populations of Kupffer cells and hepatocytes from wildtype (TK+/+) and TK-/- mice were studied. Utilizing quantitative reverse-transcription polymerase chain reaction (RT-PCR), we demonstrated that Ron is expressed in these cell types. Moreover, we also recapitulated the protected hepatocyte phenotype and exaggerated cytokine production observed in the TK-/- mice in vivo through the use of purified cultured cells ex vivo. We show that isolated TK-/- Kupffer cells produce increased levels of TNF-? and select cytokines compared to TK+/+ cells following LPS stimulation. We also show that conditioned media from LPS-treated TK-/- Kupffer cells was more toxic to hepatocytes than control media, suggesting the exaggerated levels of cytokines produced from the TK-/- Kupffer cells are detrimental to wildtype hepatocytes. In addition, we observed that TK-/- hepatocytes were more resistant to cell death compared to TK+/+ hepatocytes, suggesting that Ron functions in both the epithelial and inflammatory cell compartments to regulate acute liver injury. These findings were confirmed in vivo in mice with hepatocyte and macrophage cell-type-specific conditional Ron deletions. Mice with Ron loss selectively in hepatocytes exhibited less liver damage and increased survival compared to mice with Ron loss in macrophages. CONCLUSION:We dissected cell-type-specific roles for Ron such that this receptor modulates cytokine production from Kupffer cells and inhibits hepatocyte survival in response to injury.

Project description:BackgroundArsenic exposure has become a matter of worldwide concern, which is associated with immune-related diseases. However, little is known about its effect on inflammatory immune-related homeostasis. The purpose of our study was to understand the potential tuning of above responses exerted by chronic arsenic exposure.MethodsKunming mice were treated with 25 and 50 mg/L sodium arsenite for 1, 3 and 12 months via drinking water. At different endpoints of arsenic exposure, all animals and the whole spleen of the mice were weighed. The total arsenic levels of spleen were determined by the HPLC-HG-AFS method. Splenic NF-κB, MAPK and NRF2 protein levels by treatment of 25 mg/L NaAsO2 for 1, 3 and 12 months and 25 mg/L and 50 mg/L NaAsO2 for 12 months were assessed by western blot. Total RNA of spleen was isolated and relative mRNA levels of Foxp3, Il-10, Tnf-α, Il-6, Ifn-γ, Il-1β and Il-12 were measured by real-time PCR.ResultsOur results shown that NF-κB were continuously activated with treatment of 25 mg/L arsenic from 1, 3 to 12 months and 50 mg/L arsenic for 12 months. The transcription factor Foxp3 increased at 1 month but decreased at 3 and 12 months no matter 25 or 50 mg/L arsenic exposure. However, cytokine Il-10 always showed increased trend in mice treated with 25 or 50 mg/L arsenic for 1, 3 and 12 months. The transcriptional profiles of Tnf-α, Il-1β, Il-6, Ifn-γ and Il-12 revealed transient elevation at 1 and 3 months but shown significant decrease at 12 months on the whole. In addition, the sustained activation of inflammatory MAPK and anti-oxidative Nrf2 signaling pathways were observed in mice exposed to arsenic for 1, 3 and 12 months.ConclusionIn summary, our experiment in vivo suggested chronic arsenic exposure induces the time-dependent modulation of the inflammation and immunosuppression in spleen, which may be related to the activation of Tregs induced by MAPK/NF-κB as well as the increased transcription level of Foxp3 and Il-10.

Dataset Information

Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen.

Publications

Re-exposure to endotoxin induces differential cytokine gene expression in the rat hypothalamus and spleen.

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