Does sphingosine 1-phosphate play a protective role in the course of pulmonary tuberculosis?

University of Rome Tor Vergata, Roma, Latium, Italy
Clinical Immunology (Impact Factor: 3.67). 01/2007; 121(3):260-4. DOI: 10.1016/j.clim.2006.09.002
Source: PubMed


Sphingosine 1-phosphate (S1P) has recently been reported to induce antimycobacterial activity in vitro and in a mouse model of in vivo Mycobacterium tuberculosis infection. However, its role in the course of pulmonary tuberculosis in humans is still not known. This study shows that S1P levels in airway surface fluid of tuberculosis (TB) patients are significantly less than those observed in non-TB control patients. Moreover, the in vitro stimulation of bronchoalveolar lavage cells coming from TB patients with S1P significantly reduces intracellular growth of endogenous mycobacterial isolates. These results show that, in the course of pulmonary TB, airway epithelial fluid-associated S1P may play a protective role in the containment of intracellular mycobacterial growth and that its decrease may represent a novel pathogenic mechanism through which M. tuberculosis favors its replication.

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Available from: Prakash S Bisen,
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    • "In addition, the S1P concentration in the BAL fluid from Mycobactrium tuberculosis-infected patients has been shown to have a range of 47.5±36.2 nM (Garg et al., 2006). Thus, previous studies conducted in the presence of micromolar concentrations of S1P may not represent how S1P modulates the actions of resident AMs, since, in non-blood tissues, S1P concentrations are in the nanomolar range. "
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    ABSTRACT: The pathogenic fungus Cryptococcus neoformans is a major cause of morbidity and mortality in immunocompromised individuals. Infection of the human host occurs through inhalation of infectious propagules following environmental exposure. In the lung, C. neoformans can reside in the extracellular environment of the alveolar spaces or, upon phagocytosis, it can survive and grow intracellularly within alveolar macrophages (AMs). In previous studies, we found that sphingosine kinase 1 (SK1) influenced the intracellular residency of C. neoformans within AMs. Therefore, with this study we aimed to examine the role of the SK1 lipid product, sphingosine-1-phosphate (S1P), in the AMs-C. neoformans interaction. It was found that extracellular S1P enhances the phagocytosis of C. neoformans by AMs. Using both genetic and pharmacological approaches we further show that extracellular S1P exerts its effect on the phagocytosis of C. neoformans by AMs through S1P receptor 2 (S1P2). Interestingly, loss of S1P2 caused a dramatic decrease in the mRNA levels of Fcγ receptors I (FcγRI), -II and -III. In conclusion, our data suggest that extracellular S1P increases antibody-mediated phagocytosis through S1P2 by regulating the expression of the phagocytic Fcγ receptors.
    Microbiology 02/2011; 157(Pt 5):1416-27. DOI:10.1099/mic.0.045989-0 · 2.56 Impact Factor
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    • "Sphk-1 has been shown to regulate the MAPK signaling pathway and activates NF-kβ [20], and is highly expressed in various types of cancers [14] presumably associated with tumor angiogenesis. Recently, S1P has been shown to induce antimicrobial activity with both in vitro and in vivo animal infection models of Mycobacterium tuberculosis [21], [22], [23]. In the present investigation, we identified the involvement of Sphk-1 in the induction of β-defensin 2 in human gingival epithelial cells (HGECs) and also found that the inhibition of kinase glycogen synthase kinase-3β (GSK3-β) augments HBD-2, all of which may have therapeutic application. "
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    ABSTRACT: Host defense against invading pathogens is triggered by various receptors including toll-like receptors (TLRs). Activation of TLRs is a pivotal step in the initiation of innate, inflammatory, and antimicrobial defense mechanisms. Human beta-defensin 2 (HBD-2) is a cationic antimicrobial peptide secreted upon gram-negative bacterial perturbation in many cells. Stimulation of various TLRs has been shown to induce HBD-2 in oral keratinocytes, yet the underlying cellular mechanisms of this induction are poorly understood. Here we demonstrate that HBD-2 induction is mediated by the Sphingosine kinase-1 (Sphk-1) and augmented by the inhibition of Glycogen Synthase Kinase-3beta (GSK-3beta) via the Phosphoinositide 3-kinase (PI3K) dependent pathway. HBD-2 secretion was dose dependently inhibited by a pharmacological inhibitor of Sphk-1. Interestingly, inhibition of GSK-3beta by SB 216763 or by RNA interference, augmented HBD-2 induction. Overexpression of Sphk-1 with concomitant inhibition of GSK-3beta enhanced the induction of beta-defensin-2 in oral keratinocytes. Ectopic expression of constitutively active GSK-3beta (S9A) abrogated HBD-2 whereas kinase inactive GSK-3beta (R85A) induced higher amounts of HBD-2. These data implicate Sphk-1 in HBD-2 regulation in oral keratinocytes which also involves the activation of PI3K, AKT, GSK-3beta and ERK 1/2. Thus we reveal the intricate relationship and pathways of toll-signaling molecules regulating HBD-2 which may have therapeutic potential.
    PLoS ONE 07/2010; 5(7):e11512. DOI:10.1371/journal.pone.0011512 · 3.23 Impact Factor
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    • "Circulating undifferentiated monocytes represent both one of the targets of MTB infection and an important source of inflammatory cells that are involved in granulomatous response both in the course of active disease and latent infection [17]. Moreover, the lung is one of the organs containing the highest amount of S1P [18] and S1P concentration in the airway mucosal surfaces of TB patients has been previously reported to be significantly less than that observed in control patients [10]. Results reported herein show that S1P significantly reduces intracellular mycobacterial growth and promotes phagolysosome biogenesis in monocytes. "
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    ABSTRACT: Sphingosine 1-phosphate (S1P) has recently been described to induce antimycobacterial activity. The present study analyses the role played by S1P in antigen presentation of monocytes and in the next activation of Mycobacterium tuberculosis (MTB)-specific CD4+ T cell response. Results reported herein show that S1P stimulation of MTB-infected monocytes (i) inhibits intracellular mycobacterial growth, (ii) enhances phagolysosome maturation and the transit of mycobacteria in MHC class II compartments, (iii) increases the frequency of MTB-specific CD4+CD69+ T cells, expressing the inflammatory homing receptor CCR5, derived from tuberculosis patients and PPD+, BCG naïve, healthy subjects, and (iv) induces IFN-gamma production in CD4+CD69+CCR5+ T cells derived from PPD+ healthy individuals, only. Altogether, these results show that S1P promotes antigen processing and presentation in monocytes, increases the frequency of MTB-specific CD4+ T cells and can regulate IFN-gamma production by antigen specific CD4+ T cells in the course of active disease.
    Biochemical and Biophysical Research Communications 10/2007; 361(3):687-93. DOI:10.1016/j.bbrc.2007.07.087 · 2.30 Impact Factor
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