Cytokine and Inducible Nitric Oxide Synthase mRNA Expression during Experimental Murine Cryptococcal Meningoencephalitis

Department of Cellular and Molecular Biology, School of Medicine of Ribeirão Preto of the University of São Paulo, Ribeirão Preto, São Paulo 14049-900 Brazil.
Infection and Immunity (Impact Factor: 3.73). 05/2004; 72(4):2338-49. DOI: 10.1128/IAI.72.4.2338-2349.2004
Source: PubMed


The immune events that take place in the central nervous system (CNS) during cryptococcal infection are incompletely understood. We used competitive reverse transcription-PCR to delineate the time course of the local expression of mRNAs encoding a variety of cytokines and inducible nitric oxide synthase (iNOS) during progressive murine cryptococcal meningoencephalitis and assessed the CNS inflammatory response using immunohistochemistry. Interleukin 18 (IL-18), transforming growth factor β1, and IL-12p40 mRNAs were constitutively expressed in the brains of infected and uninfected mice; IL-2 mRNA was not detected at any time. Increased levels of transcripts corresponding to IL-1α, tumor necrosis factor alpha (TNF-α), and iNOS were detected as early as day 1 postinfection, with TNF-α rising by ∼30-fold and iNOS increasing by ∼5-fold by day 7. Each remained at these levels thereafter. IL-4, IL-6, and gamma interferon transcripts were detected on day 5, and IL-1β and IL-10 transcripts were detected beginning on day 7. Once detected, each remained at a relatively constant level through 28 days of infection. This cytokine profile does not suggest a polarized Th1 or Th2 response. Immunohistochemistry did not reveal inflammatory infiltrates before day 7, despite the presence of cryptococci. Intraparenchymal abscesses with inflammatory cells in their peripheries were found beginning on day 10. The infiltrates were comprised primarily of cells expressing CD4, CD8, or CD11b; low numbers of cells expressing CD45R/B220 were also present. The persistence of Cryptococcus observed in the CNS may result from an ineffective immune response, perhaps owing to an insufficient anticryptococcal effector function of endogenous glial cells resulting from competing pro- and anti-inflammatory cytokines. These data detail the immune response in the brain and could be important for the future design of specific immunomodulatory therapies for this important opportunistic infection.

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Available from: Karl V Clemons, May 18, 2015
    • "The 3 nitric oxide synthases (NOS) govern the production of nitric oxide and thereby its effects in PM, whereas neuronal NOS is constitutive and unchanged in PM conditions (Winkler and others 2001), endothelial NOS is upregulated in murine PM (Winkler and others 2001) and is necessary both for survival from the disease and for maintenance of blood–brain barrier (BBB) integrity (Koedel and others 2001). In contrast, and of particular relevance to our study, inducible nitric oxide synthase-2 (NOS2) is IFNg dependent (Mitchell and others 2012), highly upregulated in meningitic conditions (Reuter and others 2001; Constantin and others 2004; Maffei and others 2004), and implicated in inflammation-related BBB damage (Boje 1996; Winkler and others 2001). "

    Journal of Interferon & Cytokine Research 09/2015; DOI:10.1089/jir.2015.0078 · 2.00 Impact Factor
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    • "The innate and adaptive immunity evoked during infection in the CNS often leads to the development of neuroinflammatory diseases [1] [2] [3]. The mounting evidence suggests that neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's disease (AD), trauma, and ischemia/stroke can occur in the absence of infection. "
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    ABSTRACT: Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPARalpha, gamma, and delta isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-kappaB and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.
    PPAR Research 02/2008; 2008(1687-4757):658520. DOI:10.1155/2008/658520 · 1.64 Impact Factor
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    • "In pathologies where IL-4 or IL-13 would be present, IFN-γ induced IDO would be upregulated but WRS would be downregulated. Expression of IFN-γ and IL-4 are found simultaneously in the brain in human neurocysticercosis and mouse cryptocococcal meningoencephalitis (Maffei et al. 2004; Restrepo et al. 2001). IDO expressing cells are indeed present in granulomatous inflammation (Popov et al. 2006). "
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    ABSTRACT: Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-gamma-induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-gamma, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-gamma induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.
    Glia 10/2007; 55(13):1385-96. DOI:10.1002/glia.20544 · 6.03 Impact Factor
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