scholarly journals Regulatory Actions of Toll-Like Receptor 2 (TLR2) and TLR4 in Leishmania donovani Infection in the Liver

2013 ◽  
Vol 81 (7) ◽  
pp. 2318-2326 ◽  
Author(s):  
Henry W. Murray ◽  
Yunhua Zhang ◽  
Yan Zhang ◽  
Vanitha S. Raman ◽  
Steven G. Reed ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Leishmania Donovani ◽  
Interleukin 10 ◽  
Inos Mrna ◽  
Toll Like Receptor ◽  
Content Type ◽  
Toll Like Receptor 2 ◽  
Ifn Γ ◽  
Low Dose Chemotherapy ◽  
Oxide Synthase

ABSTRACTIn livers of susceptible but self-curing C57BL/6 mice, intracellularLeishmania donovaniinfection enhanced Toll-like receptor 4 (TLR4) and TLR2 gene expression. In the liver, infected TLR4−/−mice showed reduced gamma interferon (IFN-γ), tumor necrosis factor (TNF), and inducible nitric oxide synthase (iNOS) mRNA expression, higher-level and slowly resolving infection, delayed granuloma formation, and little response to low-dose chemotherapy; in serum, the ratio of IFN-γ to interleukin 10 (IL-10) activity was decreased by 50%. In contrast, in TLR2−/−mice, control of liver infection, parasite killing, and granuloma assembly were accelerated and chemotherapy's efficacy enhanced. In livers of infected TLR2−/−mice, mRNA expression was not increased for inflammatory cytokines or iNOS or decreased for IL-10; however, the serum IFN-γ/IL-10 ratio was increased 6.5-fold and minimal responses to IL-10 receptor blockade suggested downregulated IL-10. In established infection in wild-type mice, blockading TLR2 induced parasite killing and triggering TLR4 strengthened resistance and promoted chemotherapy's effect. Thus, in experimentalL. donovaniinfection in the liver, TLR4 signaling upregulates and TLR2 signaling downregulates macrophage antileishmanial activity, making both receptors potential therapeutic targets in visceral leishmaniasis for engagement (TLR4) or blockade (TLR2).

scholarly journals Leishmania donovani-Induced Prostaglandin E2 Generation Is Critically Dependent on Host Toll-Like Receptor 2–Cytosolic Phospholipase A2 Signaling

2016 ◽  
Vol 84 (10) ◽  
pp. 2963-2973 ◽  
Author(s):  
Amrita Bhattacharjee ◽  
Saikat Majumder ◽  
Shibali Das ◽  
Sweta Ghosh ◽  
Satabdi Biswas ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Phospholipase A2 ◽  
Leishmania Donovani ◽  
Cytosolic Phospholipase A2 ◽  
Cyclooxygenase 2 ◽  
Toll Like Receptor ◽  
Content Type ◽  
Cytosolic Phospholipase ◽  
Pge2 Release ◽  
Toll Like Receptor 2

Visceral leishmaniasis (VL) is the second-largest parasitic killer disease after malaria. During VL, the protozoanLeishmania donovaniinduces prostaglandin E2 (PGE2) generation within host macrophages to aid parasite survival. PGE2 significantly influences leishmanial pathogenesis, asL. donovaniproliferation is known to be attenuated in PGE2-inhibited macrophages. Here, we report for the first time that signaling via macrophage Toll-like receptor 2 (TLR2) plays an instrumental role in inducing PGE2 release fromL. donovani-infected macrophages. This signaling cascade, mediated via the TLR2–phosphatidylinositol 3-kinase (PI3K)–phospholipase C (PLC) signaling pathway, was found to be indispensable for activation of two major enzymes required for PGE2 generation: cytosolic phospholipase A2 (cPLA2) and cyclooxygenase 2 (Cox2). Inhibition of cPLA2, but not secreted phospholipase A2 (sPLA2) or calcium-independent phospholipase A2 (iPLA2), arrestedL. donovaniinfection. During infection, cPLA2 activity increased >7-fold in a calcium-dependent and extracellular signal-regulated kinase (ERK)-dependent manner, indicating that elevation of intracellular calcium and ERK-mediated phosphorylation was necessary forL. donovani-induced cPLA2 activation. For transcriptional upregulation of cyclooxygenase 2, activation of the calcium-calcineurin-nuclear factor of activated T cells (NFAT) signaling was required in addition to the TLR2-PI3K-PLC pathway. Detailed studies by site-directed mutagenesis of potential NFAT binding sites and chromatin immunoprecipitation (ChIP) analysis revealed that the binding of macrophage NFATc2, at the −73/−77 site on thecox2promoter, inducedL. donovani-drivencox2transcriptional activation. Collectively, these findings highlight the contribution of TLR2 downstream signaling toward activation of cPLA2 and Cox2 and illustrate how the TLR2-PI3K-PLC pathway acts in a concerted manner with calcium-calcineurin-NFATc2 signaling to modulate PGE2 release fromL. donovani-infected macrophages.

scholarly journals Toll-Like Receptor 2-Dependent Extracellular Signal-Regulated Kinase Signaling in Mycobacterium tuberculosis-Infected Macrophages Drives Anti-Inflammatory Responses and Inhibits Th1 Polarization of Responding T Cells

2015 ◽  
Vol 83 (6) ◽  
pp. 2242-2254 ◽  
Author(s):  
Edward T. Richardson ◽  
Supriya Shukla ◽  
David R. Sweet ◽  
Pamela A. Wearsch ◽  
Philip N. Tsichlis ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Erk Signaling ◽  
Toll Like Receptor ◽  
Content Type ◽  
Extracellular Signal ◽  
Toll Like Receptor 2 ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Th1 Polarization

Mycobacterium tuberculosissurvives within macrophages and employs immune evasion mechanisms to persist in the host. Protective T helper type 1 (Th1) responses are induced, and the immune response in most individuals is sufficient to restrictM. tuberculosisto latent infection, but most infections are not completely resolved. As T cells and macrophages respond, a balance is established between protective Th1-associated and other proinflammatory cytokines, such as interleukin-12 (IL-12), interferon gamma (IFN-γ), and tumor necrosis factor alpha, and anti-inflammatory cytokines, such as IL-10. The mechanisms by whichM. tuberculosismodulates host responses to promote its survival remain unclear. In these studies, we demonstrate thatM. tuberculosisinduction of IL-10, suppression of IL-12, and inhibition of class II major histocompatibility complex (MHC-II) molecules in infected macrophages are all driven by Toll-like receptor 2 (TLR2)-dependent activation of the extracellular signal-regulated kinases (ERK). Elimination of ERK signaling downstream of TLR2 by pharmacologic inhibition with U0126 or genetic deletion ofTpl2blocks IL-10 secretion and enhances IL-12 p70 secretion. We demonstrate thatM. tuberculosisregulation of these pathways in macrophages affects T cell responses to infected macrophages. Thus, genetic blockade of the ERK pathway inTpl2−/−macrophages enhances Th1 polarization and IFN-γ production by antigen-specific CD4+T cells responding toM. tuberculosisinfection. These data indicate thatM. tuberculosisand its potent TLR2 ligands activate ERK signaling in macrophages to promote anti-inflammatory macrophage responses and blunt Th1 responses against the pathogen.

scholarly journals Toll-Like Receptor 2 Agonist Pam3CSK4 Alleviates the Pathology of Leptospirosis in Hamster

2016 ◽  
Vol 84 (12) ◽  
pp. 3350-3357 ◽  
Author(s):  
Wenlong Zhang ◽  
Naisheng Zhang ◽  
Xufeng Xie ◽  
Jian Guo ◽  
Xuemin Jin ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Interleukin 10 ◽  
Peritoneal Macrophages ◽  
High Ratio ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Target Organs ◽  
Toll Like Receptor 2

Leptospirosis, caused by pathogenic spirochetes, is a zoonotic disease of global importance. The detailed pathogenesis of leptospirosis is still unclear, which limits the ideal treatment of leptospirosis. In this study, we analyzed the expression of Toll-like receptor 2 (TLR2) and TLR4 in target organs of both resistant mice and susceptible hamsters after Leptospira interrogans serovar Autumnalis infection. TLR2 but not TLR4 transcripts in mouse organs contrasted with delayed induction and overexpression in hamster organs. Coinjection of leptospires and the TLR2 agonist Pam3CSK4 into hamsters improved their survival rate, alleviated tissue injury, and decreased the abundance of leptospires in target organs. The production of interleukin-10 (IL-10) from tissues was enhanced in hamsters of the group coinjected with leptospires and Pam3CSK4 compared with the leptospira-injected group. Similarly, IL-10 levels in TLR2-deficient mice were lower than those in wild-type mice. A high ratio of IL-10/tumor necrosis factor alpha (TNF-α) levels was found in both infected wild-type mice and hamsters coinjected with leptospires and Pam3CSK4. Moreover, TLR2-dependent IL-10 expression was detected in peritoneal macrophages after leptospira infection. Our data demonstrate that coinjection of leptospires and Pam3CSK4 alleviates the pathology of leptospirosis in hamsters; this effect may result from the enhanced expression of TLR2-dependent IL-10.

scholarly journals Human Gingival CD14+ Fibroblasts Primed with Gamma Interferon Increase Production of Interleukin-8 in Response to Lipopolysaccharide through Up-Regulation of Membrane CD14 and MyD88 mRNA Expression

2002 ◽  
Vol 70 (3) ◽  
pp. 1272-1278 ◽  
Author(s):  
Riyoko Tamai ◽  
Tetsuya Sakuta ◽  
Kenji Matsushita ◽  
Mitsuo Torii ◽  
Osamu Takeuchi ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Gamma Interferon ◽  
Interleukin 8 ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Priming Effects ◽  
Regulated Expression ◽  
Toll Like Receptor 2 ◽  
Ifn Γ ◽  
Lps Signaling

ABSTRACT Gamma interferon (IFN-γ)-primed human gingival fibroblasts (HGF) have been shown to produce higher levels of interleukin-8 (IL-8) upon stimulation with bacterial products and inflammatory cytokines than nonprimed controls. In this study, we examined whether priming of HGF with IFN-γ up-regulates IL-8 production by the cells in response to purified lipopolysaccharide (LPS). The priming effect of IFN-γ was clearly observed in the high-CD14-expressing (CD14high) HGF but not in the low-CD14-expressing (CD14low) HGF. The CD14high HGF were most effectively primed with IFN-γ (1,000 IU/ml) for 72 h. To elucidate the mechanism of the priming effects of IFN-γ for the LPS response by HGF, we examined whether IFN-γ regulated expression of CD14, Toll-like receptor 2 (TLR2), TLR4, MD-2, and MyD88, all of which are molecules suggested to be associated with LPS signaling. In CD14high HGF, IFN-γ markedly up-regulated CD14 and MyD88 but not TLR4 protein and MD-2 mRNA expression, while in CD14low HGF, IFN-γ slightly increased MyD88 and scarcely affected CD14, TLR4 protein, and MD-2 mRNA levels. LPS-induced IL-8 production by IFN-γ-primed CD14high HGF was significantly inhibited by monoclonal antibodies (MAbs) against CD14 and TLR4, but not by an anti-TLR2 MAb. These findings suggested that IFN-γ primed CD14high HGF to enhance production of IL-8 in response to LPS through augmentation of the CD14-TLR system, where the presence of membrane CD14 was indispensable for the response of HGF to LPS.

scholarly journals MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Sanjay Varikuti ◽  
Gayathri Natarajan ◽  
Greta Volpedo ◽  
Bhawana Singh ◽  
Omar Hamza ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Interleukin 4 ◽  
Cytokine Signaling ◽  
T Helper 1 ◽  
Content Type ◽  
Inflammatory Monocytes ◽  
Organ Specific ◽  
Src Homology ◽  
Ifn Γ ◽  
Src Homology 2 Domain

ABSTRACT CD4+ T helper 1 (Th1) cells producing interferon gamma (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). MicroRNA 155 (miR155) promotes CD4+ Th1 responses and IFN-γ production by targeting suppressor of cytokine signaling-1 (SOCS1) and Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1) and therefore could play a role in the resolution of VL. To determine the role of miR155 in VL, we monitored the course of Leishmania donovani infection in miR155 knockout (miR155KO) and wild-type (WT) C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads than WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice, suggesting the induction of a compensatory miR155-independent antileishmanial pathway. Leishmania antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-γ than controls. Interestingly, at later time points, levels of Th2-associated interleukin-4 (IL-4) and IL-10 were also lower in miR155KO splenocyte supernatants than in WT mice. On the other hand, miR155KO mice displayed significantly higher levels of IFN-γ, iNOS, and TNF-α gene transcripts in their livers than WT mice, indicating that distinct organ-specific antiparasitic mechanisms were involved in control of L. donovani infection in miR155KO mice. Throughout the course of infection, organs of miR155KO mice showed significantly more PDL1-expressing Ly6Chi inflammatory monocytes than WT mice. Conversely, blockade of Ly6Chi inflammatory monocyte recruitment in miR155KO mice significantly reduced parasitic loads, indicating that these cells contributed to disease susceptibility. In conclusion, we found that miR155 contributes to the control of L. donovani but is not essential for infection resolution.

scholarly journals Copper-Induced Expression of a Transmissible Lipoprotein Intramolecular Transacylase Alters Lipoprotein Acylation and the Toll-Like Receptor 2 Response to Listeria monocytogenes

2019 ◽  
Vol 201 (13) ◽  
Author(s):  
Krista M. Armbruster ◽  
Gloria Komazin ◽  
Timothy C. Meredith
Keyword(s):  
Listeria Monocytogenes ◽  
Bacterial Species ◽  
Acyl Chain ◽  
Constitutive Expression ◽  
Innate Immune ◽  
Copper Resistance ◽  
Toll Like Receptor ◽  
General Role ◽  
Content Type ◽  
Toll Like Receptor 2

ABSTRACT Bacterial lipoproteins are globular proteins anchored to the extracytoplasmic surfaces of cell membranes through lipidation at a conserved N-terminal cysteine. Lipoproteins contribute to an array of important cellular functions for bacteria, as well as being a focal point for innate immune system recognition through binding to Toll-like receptor 2 (TLR2) heterodimer complexes. Although lipoproteins are conserved among nearly all classes of bacteria, the presence and type of α-amino-linked acyl chain are highly variable and even strain specific within a given bacterial species. The reason for lyso-lipoprotein formation and N-acylation variability in general is presently not fully understood. In Enterococcus faecalis, lipoproteins are anchored by an N-acyl-S-monoacyl-glyceryl cysteine (lyso form) moiety installed by a chromosomally encoded lipoprotein intramolecular transacylase (Lit). Here, we describe a mobile genetic element common to environmental isolates of Listeria monocytogenes and Enterococcus spp. encoding a functional Lit ortholog (Lit2) that is cotranscribed with several well-established copper resistance determinants. Expression of Lit2 is tightly regulated, and induction by copper converts lipoproteins from the diacylglycerol-modified form characteristic of L. monocytogenes type strains to the α-amino-modified lyso form observed in E. faecalis. Conversion to the lyso form through either copper addition to media or constitutive expression of lit2 decreases TLR2 recognition when using an activated NF-κB secreted embryonic alkaline phosphatase reporter assay. While lyso formation significantly diminishes TLR2 recognition, lyso-modified lipoprotein is still predominantly recognized by the TLR2/TLR6 heterodimer. IMPORTANCE The induction of lipoprotein N-terminal remodeling in response to environmental copper in Gram-positive bacteria suggests a more general role in bacterial cell envelope physiology. N-terminal modification by lyso formation, in particular, simultaneously modulates the TLR2 response in direct comparison to their diacylglycerol-modified precursors. Thus, use of copper as a frontline antimicrobial control agent and ensuing selection raises the potential of diminished innate immune sensing and enhanced bacterial virulence.

scholarly journals Role of Gamma Interferon in Helicobacter pylori Induction of Inflammatory Mediators during Murine Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 3295-3299 ◽  
Author(s):  
Marygorret Obonyo ◽  
Donald G. Guiney ◽  
Julia Harwood ◽  
Joshua Fierer ◽  
Sheri P. Cole
Keyword(s):  
Helicobacter Pylori ◽  
Gene Knockout ◽  
Gamma Interferon ◽  
Epithelial Cell Line ◽  
Inos Mrna ◽  
Inflammatory Protein ◽  
Ifn Γ ◽  
H Pylori ◽  
Oxide Synthase

ABSTRACT Gamma interferon (IFN-γ) has been proposed to play an important role in Helicobacter-related gastritis. Using the IFN-γ gene knockout (IFN-γ−/−) mouse model and a murine gastric epithelial cell line, GSM06, we demonstrated that Helicobacter pylori maximally induced macrophage inflammatory protein-2 (MIP-2) and inducible nitric oxide synthase (iNOS) mRNA only in wild-type mice. MIP-2 and iNOS mRNA were also induced by H. pylori in GSM06 cells. Induction of cyclooxygenase 2 mRNA through IFN-γ was demonstrated in GSM06 cells. These data indicate that IFN-γ mediates the induction of MIP-2 and iNOS mRNA expression by H. pylori in mice.

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