BackgroundTransient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior.MethodsSickness and depressive-like behavior in C57BL/6J mice were assessed by social exploration and the forced swim test, respectively. Expression of cytokines and IDO mRNA was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). Enzymatic activity of IDO was estimated as the amount of kynurenine produced from tryptophan as determined by high pressure liquid chromatography (HPLC) with electrochemical detection.ResultsIntracerebroventricular (i.c.v.) administration of LPS (100 ng) increased steady-state transcripts of TNFα, IL-6 and the inducible isoform of nitric oxide synthase (iNOS) in the hippocampus in the absence of any change in IFNγ mRNA. LPS also increased IDO expression and induced depressive-like behavior, as measured by increased duration of immobility in the forced swim test. The regulation of IDO expression was investigated using in situ organotypic hippocampal slice cultures (OHSCs) derived from brains of newborn C57BL/6J mice. In accordance with the in vivo data, addition of LPS (10 ng/ml) to the medium of OHSCs induced steady-state expression of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO enzymatic activity within 8 h post-LPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFα and IL-6 protein and activation of iNOS while IFNγ expression was undetectable.ConclusionThese data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce depressive-like behavior in the absence of detectable IFNγ. Targeting IDO itself may provide a novel therapy for inflammation-associated depression.

Background: Sonic hedgehog (Shh) and components of its signalling pathway have been identified in human prostate carcinoma and increased levels of their expression appear to correlate with disease progression and metastasis. The mechanism through which Shh signalling could promote metastasis in bone, the most common site for prostate carcinoma metastasis, has not yet been investigated. The present study determined the effect of Shh signalling between prostate cancer cells and pre-osteoblasts on osteoblast differentiation, a requisite process for new bone formation that characterizes prostate carcinoma metastasis.

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Traumatic brain injury (TBI) results in the activation of glia and the release of proinflammatory cytokines, including interleukin (IL)-1β. The response of astrocytes to mild TBI has not been well studied. We used an in vitro model of cell stretch to investigate the effects of mild mechanical insult on astrocyte injury (lactate dehydrogenase and propidium iodide), and on mediators of inflammation including IL-1β, the chemokine CX3CL1, and nitrite. Here, we tested the hypothesis that a mild mechanical insult would increase susceptibility of astrocytes to delayed exposure to IL-1β, including enhanced release of the matrix metalloproteinease-9 (MMP-9). We investigated the role of the mitogen protein-activated kinase (MAPK) pathway in these responses. Cells subjected to a mild stretch show an increase in activation of the ERK1/2 and JNK pathways, and an increase in lactate dehydrogenase (LDH), but no change in the levels of inflammatory mediators. An early increase in LDH was dependent on ERK activation. Exposure to IL-1β, or to stretch alone, did not increase MMP-9. In contrast, the combination of mild stretch followed by IL-1β resulted in greater activation of the ERK pathway compared to either stimulus alone, and also resulted in an increase in the production of MMP-9 by astrocytes. Inhibition of the ERK pathway suppressed the increase in MMP-9 induced by the combination of stretch and IL-1β treatment. These results suggest that a primary mild mechanical injury renders astrocytes more susceptible to a secondary exposure to a proinflammatory cytokine such as IL-1β via the activation of the ERK pathway, and suggest a mechanism by which a mild head injury may confer increased susceptibility to neurologic injury caused by a subsequent insult.

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