Prostaglandin E-2 inhibits Paracoccidioides brasiliensis killing by human monocytes

Human monocytes lacked fungicidal activity against high virulence strain of Paracoccidioides brasiliensis, even after IFN-gamma activation. However, monocytes treated with indomethacin exhibited an effective killing against this fungus, suggesting a role of prostaglandin E-2 (PGE(2)) in the inhibition process. Thus, the purpose of this work was to determine whether the effect of PGE2 in fungicidal activity was related with decrease on H2O2 release, the metabolite involved in P. brasiliensis killing, and changes in the levels of TNF-alpha, IL-6 and IL-10. Human monocytes challenged with the fungus produced high PGE(2) levels, which in turn inhibited the fungicidal activity of these cells by reducing H2O2 and TNF-alpha production. (C) 2007 Elsevier Masson SAS. All rights reserved.

Cellular recruitment and cytokine generation in a rat model of allergic lung inflammation are differentially modulated by progesterone and estradiol

We evaluated the role of estradiol and progesterone in allergic lung inflammation. Rats were ovariectomized (Ovx) and, 7 days later, were sensitized with ovalbumin (OA) and challenged after 2 wk with inhaled OA; experiments were performed 1 day thereafter. Ovx-allergic rats showed reduced cell recruitment into the bronchoalveolar lavage (BAL) fluid relative to sham-Ovx allergic rats, as was observed in intact allergic rats treated with ICI-182,780. Estradiol increased the number of cells in the BAL of Ovx-allergic rats, whereas progesterone induced an additional reduction. Cells of BAL and bone marrow (BM) of Ovx-allergic rats released elevated amounts of IL-10 and reduced IL-1 beta and TNF-alpha. BM cells of Ovx-allergic rats released increased amounts of IL-10 and lower amounts of IL-4. Estradiol treatment of Ovx-allergic rats decreased the release of IL-10 but increased that of IL-4 by BM cells. Estradiol also caused an increased release of IL-1 beta and TNF-alpha by BAL cells. Progesterone significantly increased the release of IL-10, IL-1 beta, and TNF-alpha by BAL cells and augmented that of IL-4 by BM cells. Degranulation of bronchial mast cells from Ovx rats was reduced after in vitro challenge, an effect reverted by estradiol but not by progesterone. We suggest that the serum estradiol-to-progesterone ratio might drive cellular recruitment, modulating the pulmonary allergy and profile of release of anti-inflammatory or inflammatory cytokines. The existence of such dual hormonal effects suggests that the hormone therapy of asthmatic postmenopausal women and of those suffering of premenstrual asthma should take into account the possibility of worsening the pulmonary conditions.

Effect of cytokines on the in vitro fungicidal activity of monocytes from paracoccidioidomycosis patients

Peripheral blood monocytes obtained from paracoccidioidomycosis patients and healthy individuals were preactivated with recombinant gamma interferon (IFN-gamma) in different concentrations (250, 500 and 1000 U/ml) and evaluated for fungicidal activity against Paracoccidiodes brasiliensis strain 18 (Pb 18, high-virulence strain) and strain 265 (Pb 265, low-virulence strain) by plating of cocultures and counting of colony-forming units, after 10 d. Monocytes from healthy individuals failed to present fungicidal activity against P. brasiliensis even after IFN-gamma activation at the three concentrations. However, patient, monocytes activated with IFN-gamma (1 000 U/ml) showed a significant fungicidal activity when compared to that obtained with non-activated or activated cells with other IFN-gamma concentrations (250 and 500 U/ml). Moreover,,patient monocytes presented higher fungicidal activity than the control, even before the activation process. These results may be explained by the activation state of patients' cells as a function of the in vivo contact with the fungus, which was confirmed by their higher capacity to release H2O2 in vitro. Unlike the results obtained with Ph 18, patient and control cells presented a significant fungicidal activity against Pb 265, after priming with IFN-gamma. These results are explained by the higher levels of TNF-alpha in supernatants of cultures challenged with Pb 265. Moreover, higher levels of the cytokine were obtained in patient cell supernatants. Taken together, our results suggest that for effective killing of P. brasiliensis by monocytes, an initial activation signal induced by IFN-gamma is necessary to stimulate the cells to produce TNF-alpha. This cytokine may be involved, through an autocrine pathway, in the final phase activation process. The effectiveness of this process seems to depend on the virulence of the fungal strain and the activation state of the challenged cells. (C) 2003 Editions scientifiques et medicales Elsevier SAS. All fights reserved.

Macrophages and mast cells control the neutrophil migration induced by dentin proteins

Dentin sialoprotein (DSP) and dentin phosphoprotein (DPP), the major dentin proteins, have been shown to induce neutrophil migration through release of IL-1beta, TNF-alpha, MIP-2, and KC. However, the sources of these mediators were not determined. Here, the roles of macrophages and mast cells (MC) in dentin-induced neutrophil accumulation were investigated. Peritoneal MC depletion or the enhancement of macrophage population increased DSP- and DPP-induced neutrophil extravasation. Moreover, supernatants from DSP- and DPP-stimulated macrophages caused neutrophil migration. The release of neutrophil chemotactic factor by macrophages was inhibited by dexamethasone or the supernatant of DSP- treated MC. Consistently, dexamethasone and the MC supernatant inhibited the production of IL-1beta, TNF-alpha, and MIP-2 by macrophages. This inhibitory activity of the DSP- stimulated MC was neutralized by anti-IL-4 and anti-IL-10 antibodies. These results indicate that dentin induces the release of the neutrophil chemotactic substance(s) by macrophages, which are down-modulated by MC-derived IL-4 and IL-10.

Conversion of immunosuppressive monotherapy from cyclosporin A to tacrolimus reverses bone loss in rats

Tacrolimus is used for transplant patients with refractory graft rejection and those with intolerance to cyclosporin (CsA), without the disfiguring adverse effects frequently attributed to CsA therapy. Since we have shown that CsA-associated bone loss can also affect alveolar bone, the purpose of this study was to evaluate the effects of conversion of monotherapy from CsA to tacrolimus on alveolar bone loss in rats. Groups of rats were treated with either CsA (10 mg/kg/day, s.c.), tacrolimus (I mg/kg/day, s.c.), or drug vehicle for 60 and 120 days, and an additional group received CsA for 60 days followed by conversion to tacrolimus for a further 60-day period. Bone-specific alkaline phosphatase (BALP), tartrate-resistent acid phosphatase (TRAP-5b), calcium (Ca2+), interleukin (IL)-1 beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) concentrations were evaluated in the serum. Analyses of bone volume, bone surface, number of osteblasts, and osteoclasts were performed. Treatment with CsA for either 60 or 120 days was associated with bone resorption, represented by lower bone volume and increased number of osteoclasts; serum BALP, TRAP-5b, IL-1 beta, IL-6, and TNF-alpha were also higher in these animals. After conversion from CsA to tacrolimus, all the altered serum markers returned to control values in addition to a significant increase of bone volume and a lower number of osteoclasts. This study shows that conversion from CsA to tacrolimus therapy leads to a reversal of the CsA-induced bone loss, which can probably be mediated by downregulation of IL-1 beta, IL-6, and TNF-alpha production.

Pulmonary Disease in Hamsters Infected with Leptospira interrogans: Histopathologic Findings and Cytokine mRNA Expressions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Anti-inflammatory intestinal activity of Abarema cochliacarpos (Gomes) Barneby & Grimes in TNBS colitis model

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Evaluation of macrophage activity and antibody production in genetically selected mice infected with Leptospira serovar pomona

The aim of the present study was to evaluate the role of macrophage activity and antibody production in experimental infection with Leptospira Pomona in mice genetically selected for high (H) or low (L) humoral immune response. To evaluate macrophage activity, reactive oxygen and nitrogen intermediates were determined. Also, the production of tumor necrosis factor (TNF-alpha) and the recovery of Leptospira-specific antibodies in the kidneys and liver were assessed; histological lesions were analyzed using the hematoxylin-eosin technique, and Leptospira antigens in tissues were determined by immunohistochemistry. Results showed that recovery of microorganisms from the analyzed organs was lower in LIV-A mice. However, HIV-A animals showed total restraint since the 14th day after infection, whereas LIV-A mice still had bacteria in the liver at the 21st post-infection day. Immune response against Pomona serovar in those lineages was characterized as high production of antibodies, mainly in late periods of the infectious process. The production of reactive oxygen and nitrogen intermediates also contributed to the elimination of Leptospira Pomona in all two lineages; H2O2 production was an important factor in HIV-A mice, as well as NO production in the LIV-A animals, mainly at the latest post-inoculation periods. The same occurred regarding TNF-alpha production. Severe renal lesions were observed at periods in which larger numbers of leptospires were isolated using the culture technique. Tissue alterations persisted in LIV-A mice, even at periods in which leptospires were not recovered. Immunohistochemistry showed to be more sensitive than culturing. However, both techniques were appropriate for the agent identification in the studied lineages. Results suggest that such lineages could represent an important model to investigate pathogenesis and immune response against the varied serovars of leptospires.

Detection of cytokines and nitric oxide synthase in skin lesions of Jorge Lobo's disease patients

Studies investigating the immunopathological aspects of Jorge Lobo's disease have shown that the inflammatory infiltrate consists mainly of histiocytes and multinucleated giant cells involving numerous yeast-like cells of Lacazia loboi, with the T lymphocytes more common than B lymphocytes and plasma cells. The quantification of cytokines in peripheral blood mononuclear cells culture supernatant has revealed alterations in the cytokines profile, characterized by predominance of a Th2 profile. In view of these findings and of the role of cytokines in cell interactions, the objective of the present study was to investigate the presence of the cytokines IL-10, TGF-ss 1 and TNF-alpha, as well as iNOS enzyme in granulomas induced by L. loboi. Histological sections obtained from skin lesions of 16 patients were analyzed by immunohistochemistry for the presence of these cytokines and iNOS. The results showed that TGF-ss 1 was the cytokine most frequently expressed by cells present in the inflammatory infiltrate, followed by IL-10. There was a minimum to discrete positivity of cells expressing TNF-alpha and iNOS. The results suggest that the presence of immunosuppressive cytokines in skin lesions of patients with the mycosis might be responsible for the lack of containment of the pathogen as demonstrated by the presence of numerous fungi in the granuloma.

Interactions between TLR2, TLR4, and mannose receptors with gp43 from Paracoccidioides brasiliensis induce cytokine production by human monocytes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Inhibitory effect of PGE(2) on the killing of Paracoccidioides brasiliensis by human monocytes can be reversed by cellular activation with cytokines

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Macrophage suppression following phagocytosis of apoptotic neutrophils is mediated by the S100A9 calcium-binding protein

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Downregulation of nuclear factor-kappa B (NF-kappa B) pathway by silibinin in human monocytes challenged with Paracoccidioides brasiliensis

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Serum titres of anti-glutamic acid decarboxylase-65 and anti-IA-2 autoantibodies are associated with different immunoregulatory milieu in newly diagnosed type 1 diabetes patients

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Influence of Tumour Condition on the Macrophage Activity in Candida albicans Infection

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)