The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice

Fraternale, Alessandra; Paoletti, Maria Filomena; Dominici, Sabrina; Caputo, Antonella; Castaldello, Arianna; Millo, Enrico; Brocca-Cofano, Egidio; Smietana, Michaël; Clayette, Pascal; Oiry, J.; Benatti, Umberto; Magnani, Mauro

doi:10.1016/j.vaccine.2010.09.033

Cited by 30 publications

(31 citation statements)

References 34 publications

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“…Consistent with the well-known reciprocal relationship between the production of IFN-␥ and IL-4 (64), the increase in IFN-␥ levels by splenocytes from infected I-152-treated mice was accompanied by decreased IL-4 levels in splenocytes from such mice. Hence, in agreement with previous in vitro and in vivo works showing that GSH levels influence IL-12 production and Th response patterns (17,18,38,39), we can conclude that in MAIDS Th1/Th2 cytokines can also be influenced by the redox state. Moreover, the molecules able to increase the intracellular GSH content can favor and inhibit Th1 and Th2 cytokines, respectively, thus reestablishing a Th1/Th2 balance.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, a prevalent Th2 immune response associated with an alternative pathway of macrophage activation was found to characterize LP-BM5 infection. The treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152), a prodrug of N-acetyl-cysteine (NAC) and beta-mercaptoethylamine (cysteamine), which was already successfully used both as an antiviral and as an immunomodulator (36)(37)(38)(39), could restore the intraorgan GSH content and a balanced Th1/Th2 response. These data show that, similarly to what happens in other viral infections (20,26,(40)(41)(42)(43)(44), a Th1/Th2 imbalance can be mediated by GSH-dependent mechanisms in MAIDS as well.…”

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confidence: 99%

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Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152),an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCEThe first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/ Th2 imbalance to be more effectively combated. Infection with the LP-BM5 murine leukemia virus causes a profound and broad immunodeficiency in susceptible mouse strains, such as C57BL/6 (B6) mice. This disease is known as murine AIDS (MAIDS) and is characterized by early polyclonal T-and B-cell activation, splenomegaly, lymphadenopathy, hypergammaglobulinemia, decreased T-and B-cell responses, increased susceptibility to opportunistic pathogens, and the development of terminal B-cell lymphomas and neurological dysfunctions (1-4). MAIDS is charact...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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show abstract

“…In particular, oxidative stress, a significant complication of T2D, interferes with glutathione levels and cellular redox homeostasis, causing damage to macromolecules, signaling, and cell viability (43). Glutathione, an abundant cellular antioxidant, is also critical for regulating many immunological functions (44,45). A link between reduced glutathione in peripheral blood mononuclear cells from diabetics and impaired IL-12 and IFN-␥ production after stimulation with B. pseudomallei has been suggested (42).…”

Section: Discussionmentioning

confidence: 99%

Impaired Early Cytokine Responses at the Site of Infection in a Murine Model of Type 2 Diabetes and Melioidosis Comorbidity

et al. 2013

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“…Antioxidants alter Th responses (32). Treatment with CoPP did not alter the production of IFN-γ or IL-17A by splenocytes stimulated with ConA, anti-CD3, or T. cruzi antigen at 9 dpi (Figure 2C).…”

Section: The Nrf2/ho-1 Inducer Copp Increases Resistance To T Cruzi mentioning

confidence: 94%

Oxidative stress fuels Trypanosoma cruzi infection in mice

Paiva¹,

Feijó²,

Dutra³

et al. 2012

J. Clin. Invest.

150

175

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The increase in intra-macrophage thiols induced by new pro-GSH molecules directs the Th1 skewing in ovalbumin immunized mice

Cited by 30 publications

References 34 publications

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Impaired Early Cytokine Responses at the Site of Infection in a Murine Model of Type 2 Diabetes and Melioidosis Comorbidity

Oxidative stress fuels Trypanosoma cruzi infection in mice

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