Attenuated Leishmania induce pro-inflammatory mediators and influence leishmanicidal activity by p38 MAPK dependent phagosome maturation in Leishmania donovani co-infected macrophages

Abstract Background: Adenosine is known as a protective and anti-inflammatory nucleoside. Angiotensin II is the main hormone of the renin-angiotensin system. It is associated with endothelial permeability, recruitment, and activation of the immune cells through induction of inflammatory mediators. Matrix metalloproteinase-9 (MMP-9) plays an important role in inflammatory processes mediated by macrophages. Objectives: Investigate whether adenosine pretreatment modulates angiotensin II-induced MMP-9 expression and activation of signaling molecules. Methods: Human monocytic U-937 cells were treated with either adenosine or angiotensin II alone or angiotensin II following a pretreatment with adenosine. Supernatants were analyzed for MMP-9 activity by zymography method. MMP-9 gene expression was analyzed using real-time PCR. Activation of inflammatory mediators IκB-α, NF-κB, JNK, p38 MAPK, and STAT3 were analyzed by a multi-target ELISA kit. Association of Protein kinase A (PKA) in adenosine effects was studied by pre-incubation with H89, a selective PKA inhibitor. Results: Treatment of the cells with angiotensin II significantly increased MMP-9 production (p <0.05). Adenosine pretreatment did not attenuate this angiotensin II effect. Angiotensin II treatment induced NF-κB, JNK and p38 activation. Pretreatment with adenosine prior to angiotensin II stimulation showed a 40% inhibitory effect on p38 induction (p <0.05). This effect was reversed by PKA inhibition. Conclusion: The present data confirmed that monocytic MMP-9 was a target gene for angiotensin II. Adenosine pretreatment did not inhibit MMP-9 increase in response to angiotensin II. However, it showed a potential inhibitory effect on angiotensin II inflammatory signaling.

Download Full-text

Obacunone causes sustained expression of MKP-1 thus inactivating p38 MAPK to suppress pro-inflammatory mediators through intracellular MIF

Journal of Cellular Biochemistry ◽

10.1002/jcb.26248 ◽

2017 ◽

Vol 119 (1) ◽

pp. 837-849 ◽

Cited By ~ 9

Author(s):

Yuan Gao ◽

Rui Hou ◽

Fen Liu ◽

Haibo Liu ◽

Qiaoling Fei ◽

...

Keyword(s):

P38 Mapk ◽

Inflammatory Mediators

Download Full-text

Quercetin interferes with iron metabolism in Leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkn053 ◽

2008 ◽

Vol 61 (5) ◽

pp. 1066-1075 ◽

Cited By ~ 45

Author(s):

G. Sen ◽

S. Mukhopadhyay ◽

M. Ray ◽

T. Biswas

Keyword(s):

Iron Metabolism ◽

Ribonucleotide Reductase ◽

Leishmania Donovani ◽

Leishmanicidal Activity

Download Full-text

Phagocytosis and Phagosome Maturation Are Regulated by Calcium in J774 Macrophages Interacting with Unopsonized Prey

Bioscience Reports ◽

10.1023/a:1022025903688 ◽

2002 ◽

Vol 22 (5-6) ◽

pp. 529-540 ◽

Cited By ~ 27

Author(s):

Katarina Tejle ◽

Karl-Eric Magnusson ◽

Birgitta Rasmusson

Keyword(s):

Leishmania Donovani ◽

Inhibitory Effect ◽

Phagosome Maturation ◽

Calcium Dependent ◽

Proper Functioning ◽

Phagosomal Maturation ◽

Macrophage Phagocytosis ◽

Dependent Processes

Phagocytosis by neutrophils, macrophages, and other professional phagocytes requires rapid remodeling of actin. Early phagosomes are surrounded by a rim of F-actin that is disassembled during phagosomoal maturation. Breakdown of periphagosomal F-actin and phagolysosome fusion are calcium dependent processes in neutrophils interacting with serum-opsonized prey, but appears to be calcium independent in macrophages interacting with serum- or IgG-opsonized prey. In the present study, we found that calcium was necessary for phagocytosis, breakdown of periphagosomal F-actin, and phagosomal maturation in J774 macrophages interacting with unopsonized prey. We also observed that lipophosphoglycan (LPG) from Leishmania donovani promastigotes required calcium to exert its inhibitory effect on macrophage phagocytosis and periphagosomal F-actin breakdown. We conclude that calcium is essential for phagocytosis, depolymerization of periphagosomal F-actin, and phagosomal maturation in J774 macrophages interacting with unopsonized prey, as well as for proper functioning of LPG.

Download Full-text

Killing of intracellular Leishmania donovani by human mononuclear phagocytes. Evidence for oxygen-dependent and -independent leishmanicidal activity.

Journal of Clinical Investigation ◽

10.1172/jci110972 ◽

1983 ◽

Vol 72 (1) ◽

pp. 32-44 ◽

Cited By ~ 95

Author(s):

H W Murray ◽

D M Cartelli

Keyword(s):

Leishmania Donovani ◽

Mononuclear Phagocytes ◽

Leishmanicidal Activity

Download Full-text

Protective Effect of (+)-Catechin Against Lipopolysaccharide Induced Inflammatory Response in RAW 264.7 Cells through Downregulation of NF-κB and p38 MAPK

10.21203/rs.3.rs-265638/v1 ◽

2021 ◽

Author(s):

MA Sunil ◽

vasudevan Sunitha ◽

Prasanthkumar Santhakumaran ◽

Mohind C. Mohan ◽

Midhun Sebastian Jose ◽

...

Keyword(s):

P38 Mapk ◽

Inflammatory Mediators ◽

Mrna Level ◽

Mitogen Activated Protein Kinase ◽

Raw 264.7 Cells ◽

Raw 264.7 ◽

Dependent Manner ◽

Plant Foods ◽

Tnf Α ◽

Cox 2

Abstract Catechin, a flavonol belonging to the flavonoid group of polyphenols is present in many plant foods. The present study was done to evaluate the effect of catechin on various inflammatory mediators using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. The effect of catechin on total cyclooxygenase (COX) activity, 5-lipoxygenase (5-LOX), myeloperoxidase, nitrite and inducible nitric oxide synthase (iNOS) level, secretion of tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were assessed in LPS-stimulated RAW 264.7 cells. The expression of COX-2, iNOS, TNF-α, nuclear factor-ĸB (NF-κB) and p38 mitogen-activated protein kinase (MAPK) genes were also investigated. The effect was further analyzed using human PBMCs by assessing the level of TNF-α and IL-10. The study demonstrated that the inflammatory mediators such as COX, 5-LOX, nitrite, iNOS, and TNF-α were significantly inhibited by catechin in a dose-dependent manner whereas IL-10 production was up-regulated in RAW 264.7 cells. Moreover, catechin down-regulated the mRNA level expression of COX-2, iNOS, TNF-α, NF-κB and p38 MAPK. The current study ratifies the beneficial effect of catechin as a dietary component in plant foods to provide protection against inflammatory diseases.

Download Full-text

Nanotized Curcumin and Miltefosine, a Potential Combination for Treatment of Experimental Visceral Leishmaniasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01169-16 ◽

2016 ◽

Vol 61 (3) ◽

Cited By ~ 27

Author(s):

Brajendra Tiwari ◽

Richa Pahuja ◽

Pradeep Kumar ◽

Srikanta Kumar Rath ◽

Kailash Chand Gupta ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Leishmania Donovani ◽

Oral Drug ◽

Hamster Model ◽

Content Type ◽

Leishmanicidal Activity ◽

Traditional Indian Medicine ◽

Indian Medicine

ABSTRACT Leishmaniasis chemotherapy remains very challenging due to high cost of the drug and its associated toxicity and drug resistance, which develops over a period of time. Combination therapies (CT) are now in use to treat many diseases, such as cancer and malaria, since it is more effective and affordable than monotherapy. CT are believed to represent a new explorable strategy for leishmaniasis, a neglected tropical disease caused by the obligate intracellular parasite Leishmania. In the present study, we investigated the effect of a combination of a traditional Indian medicine (ayurveda), a natural product curcumin and miltefosine, the only oral drug for visceral leishmaniasis (VL) using a Leishmania donovani-hamster model. We developed an oral nanoparticle-based formulation of curcumin. Nanoformulation of curcumin alone exhibited significant leishmanicidal activity both in vitro and in vivo. In combination with miltefosine, it exhibited a synergistic effect on both promastigotes and amastigotes under in vitro conditions. The combination of these two agents also demonstrated increased in vivo leishmanicidal activity accompanied by increased production of toxic reactive oxygen/nitrogen metabolites and enhanced phagocytic activity. The combination also exhibited increased lymphocyte proliferation. The present study thus establishes the possible use of nanocurcumin as an adjunct to antileishmanial chemotherapy.

Download Full-text

High-Salt Enhances the Inflammatory Response by Retina Pigment Epithelium Cells following Lipopolysaccharide Stimulation

Mediators of Inflammation ◽

10.1155/2015/197521 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Dike Zhang ◽

Chaokui Wang ◽

Shuang Cao ◽

Zi Ye ◽

Bolin Deng ◽

...

Keyword(s):

Transcription Factors ◽

Autoimmune Disease ◽

Osmotic Stress ◽

P38 Mapk ◽

Inflammatory Mediators ◽

Pigment Epithelium ◽

High Salt ◽

Stress Control ◽

Epithelium Cells ◽

Retina Pigment Epithelium

High-salt has been shown to play a role in the pathogenesis of autoimmune disease. In this study, we investigated the effect of high-salt on the production of inflammatory mediators by ARPE-19 cells and the possible mechanisms involved. ARPE-19 cells were cultured with LPS in DMEM to which extra NaCl had been added (20 mM and 40 mM). NaCl had no influence on the apoptosis and proliferation of ARPE-19. Addition of 40 mM NaCl significantly induced IL-6 and MCP-1 production but had no effect on IL-8 secretion. High mannitol, as an osmotic stress control, did not affect the secretion of inflammatory mediators by ARPE-19 cells indicating that the effect was not mediated by osmolarity. Coculture of ARPE-19 cells with NaCl resulted in significant increases in the phosphorylation of p38 MAPK, Akt, and NF-κB and an upregulation of the transcription factors NFAT5 and SGK1. High-salt significantly promotes IL-6 and MCP-1 production by ARPE-19 cells and is associated with activation of the p38 MAPK, Akt, and NF-κB pathway and NFAT-SGK1 pathways.

Download Full-text

Bigelovii A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Blocking NF-κB and CCAAT/Enhancer-Binding ProteinδPathways

Mediators of Inflammation ◽

10.1155/2016/9201604 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Chunguang Yan ◽

Fuqin Guan ◽

Yanfei Shen ◽

Huifang Tang ◽

Dong Yuan ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

P38 Mapk ◽

Inflammatory Mediators ◽

Neutrophil Infiltration ◽

Therapeutic Approaches ◽

Lps Challenge ◽

Enhancer Binding Protein ◽

Underlying Mechanisms

Optimal methods are applied to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), but the mortality rate is still high. Accordingly, further studies dedicated to identify novel therapeutic approaches to ALI are urgently needed. Bigelovii A is a new natural product and may exhibit anti-inflammatory activity. Therefore, we sought to investigate its effect on lipopolysaccharide- (LPS-) induced ALI and the underlying mechanisms. We found that LPS-induced ALI was significantly alleviated by Bigelovii A treatment, characterized by reduction of proinflammatory mediator production, neutrophil infiltration, and lung permeability. Furthermore, Bigelovii A also downregulated LPS-stimulated inflammatory mediator expressionsin vitro. Moreover, both NF-κB and CCAAT/enhancer-binding proteinδ(C/EBPδ) activation were obviously attenuated by Bigelovii A treatment. Additionally, phosphorylation of both p38 MAPK and ERK1/2 (upstream signals of C/EBPδactivation) in response to LPS challenge was also inhibited by Bigelovii A. Therefore, Bigelovii A could attenuate LPS-induced inflammation by suppression of NF-κB, inflammatory mediators, and p38 MAPK/ERK1/2—C/EBPδ, inflammatory mediators signaling pathways, which provide a novel theoretical basis for the possible application of Bigelovii A in clinic.

Download Full-text