The aim of the present study was to examine the in vivo effect of interleukin (IL)-12 on a murine model of asthma induced by Dermatophagoides pteronyssinus-derived Der p 1 allergen. C57BL/6 mice immunized with Der p 1 allergen adsorbed to alum/pertussis toxin developed a T-helper type 2 (Th2)-dominant immune response characterized by the presence of IgE antibody, airway eosinophil infiltration and increased production of Th2 cytokine. Intraperitoneal injection of IL-12 (1 or 0.1 microg per day) for 5 days (day -1 to +3) simultaneously with each immunization, inhibited the production of IgE and IgG1 antigen-specific antibodies, whereas production of IgG2a was strongly enhanced. In addition, mice receiving both doses of IL-12 showed a strong inhibition of IL-5 but up-regulation of IFN-gamma production by spleen cells stimulated with antigen. Administration of IL-12 also prevented antigen-induced eosinophil infiltration into the bronchoalveolar area in a dose-dependent manner and the primary inflammatory mediator serotonin in bronchoalveolar lavage (BAL) fluids was also reduced significantly. Taken together, the data indicate that IL-12 has a potent immunomodulatory effect on house-dust-mite-induced allergic disorders and may be used as an efficient agent for immunotherapy.
Our data showed that the intratracheal transfer of the IL-10 gene could affect the recruitment of inflammatory cells during the challenge phase in a way that would result in the inhibition of airway inflammation. These findings suggest that the development of an immunoregulatory strategy based on IL-10 might shed light on more effective treatment.
No abstract
Background: Schistosoma haematobium, the helminth causing urogenital schistosomiasis, is a known bladder carcinogen. Despite the causal link between S. haematobium and bladder cancer, the underlying mechanisms are poorly understood. S. haematobium oviposition in the bladder is associated with angiogenesis and urothelial hyperplasia. These changes may be pre-carcinogenic events in the bladder. We hypothesized that the Interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE), an S. haematobium egg-secreted “infiltrin” protein that enters host cell nuclei to alter cellular activity, is sufficient to induce angiogenesis and urothelial hyperplasia. Methods: Mouse bladders injected with S. haematobium eggs were analyzed via microscopy for angiogenesis and urothelial hyperplasia. Endothelial and urothelial cell lines were incubated with recombinant IPSE protein or an IPSE mutant protein that lacks the native nuclear localization sequence (NLS-) and proliferation measured using CFSE staining and real-time monitoring of cell growth. IPSE’s effects on urothelial cell cycle status was assayed through propidium iodide staining. Endothelial and urothelial cell uptake of fluorophore-labeled IPSE was measured. Findings: Injection of S. haematobium eggs into the bladder triggers angiogenesis, enhances leakiness of bladder blood vessels, and drives urothelial hyperplasia. Wild type IPSE, but not NLS-, increases proliferation of endothelial and urothelial cells and skews urothelial cells towards S phase. Finally, IPSE is internalized by both endothelial and urothelial cells. Interpretation: IPSE drives endothelial and urothelial proliferation, which may depend on internalization of the molecule. The urothelial effects of IPSE depend upon its NLS. Thus, IPSE is a candidate pro-carcinogenic molecule of S. haematobium.
19IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with 20 Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. 21The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in 22 the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but 23 associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis 24 by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra -/-) and wild type mice with S. 25 haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial 26 proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial 27 cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream 28 regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of 29 granulomatous responses to bladder-wall injected S. haematobium eggs in Il4ra -/versus wild type mice. 30 S. haematobium egg injection triggered significant urothelial proliferation, including evidence of 31 urothelial hyperdiploidy and cell cycle skewing in wild type but not Il4ra -/mice. Urothelial exposure to 32 IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 33 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular 34 aspects of this signaling pathway may exert these effects directly on the urothelium. These findings 35 point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis. 36 37 unfortunately sets the stage for the characteristic fibrotic response. For intestinal schistosomiasis, 48 hepatosplenomegaly and portal hypertension may result, or bladder cancer in the case of urogenital 49 schistosomiasis. 50The exact underlying mechanism by which schistosome eggs induce IL-4 production/release is still 51 uncertain [2]. The major sources of IL-4 have also been shown to include other sources beyond the Th2 52 cells themselves [14]. Parasite egg crude extract has been shown to stimulate enormous IL-4 release 53 from basophils [2, 15], mast cells and other non-T-cell, non-B-cell populations [16], which may indeed 54 represent constitutive sources of IL-4, apart from the Th2 cells. Other Fcε receptor negative non-55 lymphocyte sources of IL-4 have also been reported [17, 18]. The most abundant IL-4 inducing egg 56 antigen has since been identified and characterized from S. mansoni and S. haematobium [2, 15, 19, 20]. 57The interleuking-4 inducing principle from Schistosoma eggs (IPSE) binds to IgE on the surface of these 58 non-T-cell sources, inducing massive IL-4 release that subsequently drive type-2 response [2, 15, 19, 59 20]. 60Although the role of IL-4 in driving schistosomiasis-induced pathogenesis is widely studied for hepato-61 splenic schistosomi...
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