Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

Patton, Elisabeth A.; Flamme, Anne Camille La; Pedras-Vasoncelos, Joao A.; Pearce, Edward J.

doi:10.1128/iai.70.1.177-184.2002

Cited by 25 publications

(23 citation statements)

References 52 publications

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“…iNOS, which produces nitric oxide from L-arginin, is induced during the immune response by microbial products and/or cytokines and is also involved in the anti-microbial effector mechanism of macrophages (10) . One of the T-helper 1 effector mechanisms mediated by IFN-g is iNOS induction, and IL-4 plays an important role as its regulator (11) . High numbers of iNOS (+) cells have been shown in tumour-bearing mice (DMH group), suggesting an increase in nitric oxide production by these cells.…”

Section: Yoghurt and Colon Cancermentioning

confidence: 99%

The application of probiotic fermented milks in cancer and intestinal inflammation

LeBlanc

Perdigón

2010

Proc. Nutr. Soc.

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Lactic acid bacteria are present in many foods such as yoghurt and are frequently used as probiotics to improve some biological functions of the host. Many researchers have evaluated the effects of yoghurt and lactic acid bacteria against diseases such as cancer and intestinal inflammation. The preventive effect of probiotics on intestinal carcinogenesis may be associated with changes in the intestinal microbiota, suppressing the growth of bacteria that convert procarcinogens into carcinogens. Other mechanisms could be related to the immune response modulation and have been evaluated using milks fermented with lactic acid bacteria in chemically induced colon cancer and hormone-dependent breast cancer models. We demonstrated, using a murine colon cancer model, that yoghurt consumption inhibited tumour growth by decreasing the inflammatory response by increasing IL-10-secreting cells, cellular apoptosis and diminishing procarcinogenic enzymes. Milk fermented with Lactobacillus helveticus R389 delayed breast tumour growth by decreasing IL-6 and increasing IL-10 in serum and in the mammary glands and tumour-infiltrating immune cells. Previous results obtained with yoghurt administration in a colon cancer model led us to analyse its effect on a trinitrobenzenesulfonic acid-induced intestinal inflammation model in mice. Yoghurt was able to attenuate the symptoms of acute inflammation by reducing inflammatory cytokines, and increasing regulatory cytokine IL-10-producing cells, leading to desirable changes of the intestinal microbiota. It was demonstrated, by using murine models, that the consumption of fermented milks can modulate the immune system and can maintain it in a state of surveillance, which could affront different pathologies such as cancer and intestinal inflammation.

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Section: Yoghurt and Colon Cancermentioning

confidence: 99%

The application of probiotic fermented milks in cancer and intestinal inflammation

LeBlanc

Perdigón

2010

Proc. Nutr. Soc.

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“…Although the exact mechanism of IL-4 action in this system remains to be elucidated, a possible explanation for the ad- For example, IL-4 may inhibit macrophage-dendritic cell antiHistoplasma function by decreasing iNOS production or stimulating production of other cytokines that inhibit protection (26). Future experiments will examine the role of IL-4 on protective cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination ofHistoplasma capsulatum

et al. 2003

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Protection against the pathogenic fungus Histoplasma capsulatum requires Th1 cytokines. Since interleukin-4 (IL-4) can inhibit both Th1 cytokine production and activity, we examined the effects of overproduction of IL-4 in the lung on the course of pulmonary histoplasmosis. IL-4 lung transgenic mice manifested a higher fungal burden in their lungs, but not spleens, compared to wild-type infected controls. Despite the higher burden, the transgenic animals were ultimately capable of controlling infection. The adverse effects of IL-4 on H. capsulatum elimination were not observed during the early phase of infection (days 1 to 3) but were maximal at day 7 postinfection, prior to the induction of cell-mediated immunity. Analysis of total body and lung cytokine levels revealed that gamma interferon and tumor necrosis factor alpha production were not inhibited in the presence of excess IL-4. Our results with transgenic mice were supported by additional in vivo studies in which allergen induction of pulmonary IL-4 was associated with delayed clearance of H. capsulatum yeast and increased fungal burden. These findings demonstrate that excess production of endogenous IL-4 modulates protective immunity to H. capsulatum by delaying clearance of the organism but does not prevent the generation of a Th1 response that ultimately controls infection.

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“…19 Because IL-4 and IL-13 use the IL-4Ra chain for cell activation and are known regulators of NOS-2 expression, 20 we determined whether the absence of IL-4/IL-13 signaling affected NO production in our system. Although similar levels of NO were detected in splenocyte cultures from WT and IL-4Ra À/À mice 8 d.p.i., the absence of IL-4Ra led to a greater production of NO by splenocytes from mice 4 d.p.i.…”

Section: Il-4ra à/à Macrophages and Tregs Inhibit Eae P Keating Et Almentioning

confidence: 99%

Protection from EAE by IL‐4Rα^−/− macrophages depends upon T regulatory cell involvement

et al. 2009

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The administration of Th2 cytokines or immune deviation to a Th2 phenotypic response has been shown to protect against the autoimmune pathology of experimental autoimmune encephalomyelitis (EAE). To better understand the function of Th2 cytokines in the induction stage of EAE in the absence of an overt Th2 response, we immunized IL-4 receptor alpha-deficient (IL-4Ra À/À ) mice, which are unable to respond to either IL-4 or IL-13. Contrary to expectations, mice lacking IL-4Ra had a lower incidence of EAE and a delayed onset compared to WT BALB/c mice; however, this delay did not correlate to an alteration in the Th1/Th17 cytokine balance. Instead, IL-4Ra-responsive macrophages were essential promoters of disease as macrophagespecific IL-4Ra-deficient (LysM cre IL-4Ra À/lox ) mice were protected from EAE. The protection afforded by IL-4Ra-deficiency was not due to IL-10-, IFN-c-, NO-or IDO-mediated suppression of T-cell responses but was dependent upon the presence of regulatory T cells (Tregs). This investigation highlights the importance of macrophages and Tregs in regulating central nervous system inflammation and demonstrates that macrophages activated in the absence of Th2 cytokines can promote disease suppression by Tregs. Keywords: EAE; macrophage; IL-4Ra; T regulatory cell; immune regulation Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), models aspects of MS including autoimmune Th response development and central nervous system (CNS) inflammation. Mice immunized with myelin proteins or immunodominant peptides of myelin develop an ascending progressive paralysis mediated by CD4 T cells, 1 and migration of these myelin-specific CD4 cells to the CNS induces inflammation, demyelination and axonal/ neuronal damage. 2 Autoreactive CD4 T cells are essential in triggering EAE; however, macrophages are required to facilitate the invasion of the autoreactive T cells into the CNS parenchyma and are thus also essential in the development of autoimmune pathology. 3 Macrophage depletion or deactivation completely blocks the egress of T cells from the perivascular spaces into the parenchyma thus preventing the disease-causing demyelination and tissue damage. 3 Conversely, mice that exhibit greater numbers of activated macrophages have been shown to develop a more rapid onset of EAE. 4 Cytokines produced by Th2 cells (especially IL-4) have been associated with remission from EAE, 5 and the levels of the Th2-associated cytokines, IL-4 and IL-10, are increased within the CNS during recovery from EAE. 6 Moreover, administration of IL-4 or immune deviation to enhance Th2 cell development can reduce or inhibit EAE. 7-9 Using mice deficient in the STAT6 pathway, which controls the differentiation of cells into a Th2 phenotype, a more severe course of EAE develops establishing a regulatory function for Th2 cytokines in vivo during EAE. 10 However, despite the protective effect of Th2 cytokines in EAE and MS, a recent study has shown that IL-4 receptor alpha-deficient (IL-4Ra À/À ) m...

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Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

Cited by 25 publications

References 52 publications

The application of probiotic fermented milks in cancer and intestinal inflammation

The application of probiotic fermented milks in cancer and intestinal inflammation

Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination ofHistoplasma capsulatum

Protection from EAE by IL‐4Rα^−/− macrophages depends upon T regulatory cell involvement

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Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

Cited by 25 publications

References 52 publications

The application of probiotic fermented milks in cancer and intestinal inflammation

The application of probiotic fermented milks in cancer and intestinal inflammation

Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination ofHistoplasma capsulatum

Protection from EAE by IL‐4Rα−/− macrophages depends upon T regulatory cell involvement

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Protection from EAE by IL‐4Rα^−/− macrophages depends upon T regulatory cell involvement