scholarly journals Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Mycobacterium smegmatis-Induced Cytokine Production by Human Macrophages In Vitro

2001 ◽  
Vol 69 (3) ◽  
pp. 1433-1439 ◽  
Author(s):  
Frank A. Post ◽  
Claudia Manca ◽  
Olivier Neyrolles ◽  
Bernhard Ryffel ◽  
Douglas B. Young ◽  
...  

ABSTRACT Vaccination of mice with Mycobacterium vaccae orM. smegmatis induces some protection against M. tuberculosis challenge. The 19-kDa lipoprotein of M. tuberculosis, expressed in M. vaccae or M. smegmatis (M. smeg19kDa), abrogates this protective immunity. To investigate the mechanism of this suppression of immunity, human monocyte-derived macrophages (MDM) were infected with M. smeg19kDa. Infection resulted in reduced production of tumor necrosis factor alpha (TNF-α) (P < 0.01), interleukin-12 (IL-12) (P < 0.05), IL-6 (P < 0.05), and IL-10 (P < 0.05), compared to infection with M. smegmatis vector (M. smegV). Infection with M. smeg19kDa and with M. smegV had no differential effect on expression of costimulatory molecules on MDM, nor did it affect the proliferation of presensitized T cells cocultured with infected MDM. When MDM were infected withM. smegmatis expressing mutated forms of the 19-kDa lipoprotein, including non-O-glycosylated (M. smeg19NOG), nonsecreted (M. smeg19NS), and nonacylated (M. smeg19NA) variants, the reduced production of TNF-α or IL-12 was not observed. When the purified 19-kDa lipoprotein was added directly to cultures of infected monocytes, there was little effect on either induction of cytokine production or its inhibition. Thus, the immunosuppressive effect is dependent on glycosylated and acylated 19-kDa lipoprotein present in the phagosome containing the mycobacterium. These results suggest that the diminished protection against challenge with M. tuberculosis seen in mice vaccinated with M. smegmatis expressing the 19-kDa lipoprotein is the result of reduced TNF-α and IL-12 production, possibly leading to reduced induction of T-cell activation.

2002 ◽  
Vol 70 (9) ◽  
pp. 5216-5224 ◽  
Author(s):  
Barbara A. Butcher ◽  
Eric Y. Denkers

ABSTRACT Macrophages (Mφ) infected with tachyzoites of the opportunistic protozoan Toxoplasma gondii are blocked in production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12) in response to lipopolysaccharide (LPS) triggering, and this is associated with parasite-induced inhibition of NFκB translocation. Here, we demonstrate a requirement for active invasion in the ability of the parasite to mediate suppression. Neither soluble tachyzoite antigen nor secreted products were suppressive, and heat-inactivated, antibody-coated tachyzoites, which efficiently entered the cell through receptor-mediated uptake, failed to inhibit LPS responses. Cytochalasin D, a drug blocking tachyzoite invasion of, but not adherence to, Mφ, severely curtailed Toxoplasma-induced suppression. In addition, parasite-induced nonresponsiveness, as measured by TNF-α production, was reversed by treating infected cells with the toxoplasmastatic drugs pyrimethamine and 6-thioxanthine prior to LPS stimulation. A divergence in IL-12 and TNF-α responses was found during extended incubation of tachyzoites and Mφ in that 24 h of incubation of infected Mφ resulted in IL-12, but not TNF-α, secretion, and production of the latter cytokine remained suppressed when these cells were subjected to LPS triggering. Our results demonstrate that active invasion and survival of the parasite within the parasitophorous vacuole are required to induce and maintain Mφ cytokine-specific nonresponsiveness to LPS. They also show that the effects of Toxoplasma on IL-12 and TNF-α production are nonidentical, with the parasite exerting a longer-lasting suppression of the latter.


2003 ◽  
Vol 12 (6) ◽  
pp. 323-328 ◽  
Author(s):  
Shigeru Abe ◽  
Naho Maruyama ◽  
Kazumi Hayama ◽  
Hiroko Ishibashi ◽  
Shigeharu Inoue ◽  
...  

Background:In aromatherapy, essential oils are used as anti-inflammatory remedies, but experimental studies on their action mechanisms are very limited.Aims:To assess their anti-inflammatory activities, effects of essential oils on neutrophil activation were examinedin vitro.Methods:Neutrophil activation was measured by tumor necrosis factor-alpha (TNF-α)-induced adherence reaction of human peripheral neutrophils.Results:All essential oils tested at 0.1% concentration suppressed TNF-α-induced neutrophil adherence, and, in particular, lemongrass, geranium and spearmint oils clearly lowered the reaction even at 0.0125%. Similar inhibitory activities for the neutrophil adherence were obtained by their major constituent terpenoids: citral, geraniol, citronellol and carvone. In contrast, very popular essential oils, tea tree oil and lavender oil, did not display the inhibitory activity at the concentration.Conclusion:Thus, some essential oils used as anti-inflammatory remedies suppress neutrophil activation by TNF-α at a low concentration (0.0125-0.025%)in vitro.


Author(s):  
Md Sarfaraz Alam ◽  
Mohamammad Daud Ali ◽  
Md Salahuddin Ansari ◽  
Pankaj Sharma

Objective: The main objective of our study is to explore anti-inflammatory activity at its molecular level like tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12) expression, and histopathological study.Methods: As per solubility/miscibility of clobetasol propionate (CP) with tea tree oil (TTO), surfactant and cosurfactant (Smix), and water in a ratio of oil:Smix:water (15:35:50) taken in milliliter for the preparation of nanoemulsion. Induced allergic contact dermatitis (ACD) with dinitrofluorobenzene (DNFB) was used for the study. TNF-α and interleukin 12 (IL-12) were estimated with rabbit antimouse TNF-α and rat antimouse IL-12 antibodies in 1% of bovine serum albumin in phosphate buffer.Results: Topical application of CP loaded nanoemulsion gel inhibits ear inflammation and erythema in DNFB-induced ACD in mice and significantly reduces the intracellular edema and infiltration with inflammatory mediator cells involving of mononuclear cells and neutrophils. CP loaded nanoemulsion gel reduces expression of protein level of TNF-α and IL-12.Conclusion: CP loaded nanoemulsion gel confirmed that anti-inflammatory effects showed more rapidly than the placebo and marketed gel preparation. However, the animals treated with placebo nanoemulsion gel showed a somehow comparable reduction of their inflammation during treatment compared with the marketed gel. This effect may be due to anti-inflammatory effect of TTO. This result suggested that anti-inflammatory activity of placebo nanoemulsion gel may be due to TTO present in nanoemulsion as vehicle.


2001 ◽  
Vol 69 (4) ◽  
pp. 2162-2171 ◽  
Author(s):  
Lisl K. M. Shoda ◽  
Kimberly A. Kegerreis ◽  
Carlos E. Suarez ◽  
Isabel Roditi ◽  
Ricardo S. Corral ◽  
...  

ABSTRACT The activation of innate immune responses by genomic DNA from bacteria and several nonvertebrate organisms represents a novel mechanism of pathogen recognition. We recently demonstrated the CpG-dependent mitogenic activity of DNA from the protozoan parasiteBabesia bovis for bovine B lymphocytes (W. C. Brown, D. M. Estes, S. E. Chantler, K. A. Kegerreis, and C. E. Suarez, Infect. Immun. 66:5423–5432, 1998). However, activation of macrophages by DNA from protozoan parasites has not been demonstrated. The present study was therefore conducted to determine whether DNA from the protozan parasites B. bovis, Trypanosoma cruzi, and T. brucei activates macrophages to secrete inflammatory mediators associated with protective immunity. DNA fromEscherichia coli and all three parasites stimulated B-lymphocyte proliferation and increased macrophage production of interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-α), and nitric oxide (NO). Regulation of IL-12 and NO production occurred at the level of transcription. The amounts of IL-12, TNF-α, and NO induced by E. coli and protozoal DNA were strongly correlated (r 2 > 0.9) with the frequency of CG dinucleotides in the genome, and immunostimulation by DNA occurred in the order E. coli ≥ T. cruzi > T. brucei > B. bovis. Induction of inflammatory mediators by E. coli, T. brucei, and B. bovis DNA was dependent on the presence of unmethylated CpG dinucleotides. However, at high concentrations,E. coli and T. cruzi DNA-mediated macrophage activation was not inhibited following methylation. The recognition of protozoal DNA by B lymphocytes and macrophages may provide an important innate defense mechanism to control parasite replication and promote persistent infection.


1998 ◽  
Vol 42 (7) ◽  
pp. 1605-1609 ◽  
Author(s):  
Marc J. Schultz ◽  
Peter Speelman ◽  
Sebastian Zaat ◽  
Sander J. H. van Deventer ◽  
Tom van der Poll

ABSTRACT To determine the effects of penicillin and erythromycin on cytokine production induced by heat-killed Streptococcus pneumoniae (HKSP), we studied the effects of those drugs on cytokine production induced by S. pneumoniaein human whole blood in vitro and ex vivo. In whole blood in vitro, erythromycin, but not penicillin, caused a dose-dependent decrease in HKSP-induced production of tumor necrosis factor alpha (TNF) and interleukin 6 (IL-6), while the production of IL-10, IL-12, and gamma interferon was inhibited only at the highest erythromycin concentration tested (10−3 M). The production of TNF and IL-6 in whole blood obtained from healthy subjects after a 30-min infusion of erythromycin (1,000 mg) was lower after ex vivo stimulation with HKSP than that in blood drawn before the infusion. Inhibition of TNF contributed to erythromycin-induced inhibition of IL-6 synthesis. Inhibition of TNF and IL-6 production by erythromycin may have a negative impact on host defense mechanisms during pneumococcal pneumonia.


2006 ◽  
Vol 24 (13) ◽  
pp. 2105-2112 ◽  
Author(s):  
Sandra J. Strauss ◽  
Lenushka Maharaj ◽  
Susan Hoare ◽  
Peter W. Johnson ◽  
John A. Radford ◽  
...  

Purpose To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. Patients and Methods Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-α) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. Results Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-α of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07). Conclusion Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-α and in vitro sensitivity in a small number of patients.


2011 ◽  
Vol 79 (4) ◽  
pp. 1638-1646 ◽  
Author(s):  
Natália B. Carvalho ◽  
Fernanda S. Oliveira ◽  
Fernanda V. Durães ◽  
Leonardo A. de Almeida ◽  
Manuela Flórido ◽  
...  

ABSTRACTTo investigate the role of Toll-like receptor 9 (TLR9) in innate immunity toMycobacteriumavium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control ofM.aviuminfection. However, TLR9 KO or TLR2 KO spleen cells displayed normalM.avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4+T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production byM.avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes inM.avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control ofM.aviuminfection is not related to the induction of Th1 responses.


2005 ◽  
Vol 73 (12) ◽  
pp. 8437-8441 ◽  
Author(s):  
Hyosun Cho ◽  
David N. McMurray

ABSTRACT Neutralization of tumor necrosis factor alpha (TNF-α) significantly down-regulated antigen-induced lymphoproliferation and the expression of interleukin-12 p40 and gamma interferon mRNA and enhanced the viability of intracellular attenuated and virulent mycobacteria in cocultures of immune T cells and macrophages obtained from Mycobacterium bovis BCG-vaccinated guinea pigs. This suggests the crucial role of TNF-α in the activation of a type 1 T-cell response against Mycobacterium tuberculosis infection.


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