Increased Survival in Sepsis by In Vivo Adenovirus-Induced Expression of IL-10 in Dendritic Cells

Oberholzer, Andreas; Oberholzer, Caroline; Bahjat, Keith S.; Ungaro, Ricardo; Tannahill, Cynthia L.; Murday, Michelle; Bahjat, Frances R.; Abouhamze, Zaher; Tsai, Van; LaFace, Drake; Hutchins, Beth; Moldawer, Lyle L.; Clare‐Salzler, Michael

doi:10.4049/jimmunol.168.7.3412

Cited by 53 publications

(50 citation statements)

References 36 publications

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“…In two previous reports, we observed that the in vivo transfection of DCs with an adenoviral recombinant expressing IL-10 generated a regulatory-like DC population that protected mice from CLP-induced mortality (17,23). Interestingly, similar improvements in outcome could be obtained when the animals received adoptive transfer of DCs transduced ex vivo to produce IL-10 (26).…”

Section: Discussionmentioning

confidence: 63%

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CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Scumpia¹,

McAuliffe²,

O’Malley³

et al. 2005

The Journal of Immunology

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CD11c+ dendritic cells (DCs) are APCs that link innate and adaptive immunity. Although DCs are lost from spleen and lymph nodes in sepsis, their role in outcome remains unclear. Transgenic mice (B6.FVB-Tg.Itgax-DTR/EGFP.57Lan/J) expressing the diphtheria toxin (DT) receptor on the CD11c promoter (DCKO mice) received 4 ng/kg DT, which resulted in depletion of 88–95% of mature myeloid and lymphoid DCs, with less depletion (75%) of plasmacytoid DCs. Pretreatment of DCKO mice with DT resulted in reduced survival in sepsis compared with saline-pretreated DCKO mice (0 vs 54%; p < 0.05) or DT-treated wild-type littermates (0 vs 54%; p < 0.05). This increased mortality was not associated with either increased bacteremia or plasma cytokine concentrations. Intravenous injection of 107 wild-type DCs improved survival in DCKO mice (42 vs 0%; p = 0.05). These data confirm that DCs are essential in the septic response and suggest that strategies to maintain DC numbers or function may improve outcome.

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Section: Discussionmentioning

confidence: 63%

“…For induction of polymicrobial sepsis, mice (n ϭ 11 per treatment group) were subjected to CLP as previously described (16,17). In brief, laparotomy was performed, and the cecum was isolated, ligated, and punctured through and through with a 22-gauge needle.…”

Section: Cecal Ligation and Puncturementioning

confidence: 99%

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Scumpia¹,

McAuliffe²,

O’Malley³

et al. 2005

The Journal of Immunology

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“…First, one injection of Ad-shNUCB2 may not be enough for significantly knocking down central nesfatin-1/NUCB2. Because adenovirus-mediated gene expression was considered to be dose and time dependent in a linear fashion (23,24), multiple injections to increase vector dose may be required for a large effect on gene expression and, consequently, on the food intake. Second, there was insufficient blockade (50%) of NUCB2 translation at key hypothalamic nuclei related to food intake.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic Nesfatin-1/NUCB2 Knockdown Augments Hepatic Gluconeogenesis That Is Correlated With Inhibition of mTOR-STAT3 Signaling Pathway in Rats

Yang

Chen

et al. 2014

Diabetes

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Nesfatin-1, an 82-amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats through an adenoviral-mediated RNA interference. With this model, we found that inhibition of central nesfatin-1/NUCB2 activity markedly increased food intake and hepatic glucose flux and decreased glucose uptake in peripheral tissue in rats fed either a normal chow diet (NCD) or a highfat diet (HFD). The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of glucose-6-phosphatase and PEPCK and decreased insulin receptor, insulin receptor substrate 1, and AKT kinase phosphorylation. Furthermore, knockdown of hypothalamic nesfatin-1 led to decreased phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) and the subsequent suppressor of cytokine signaling 3 levels. These results demonstrate that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which is, at least in part, associated with the activation of the mTOR-STAT3 signaling pathway. Diabetes 2014;63:123463: -124763: | DOI: 10.2337 The hypothalamus, where numerous neuropeptides and transmitters are released to control essential body functions, has been considered a key integrator in the central control of food intake and energy balance (1,2). Oh-I et al. (3) discovered nesfatin-1, an 82-amino acid polypeptide, while searching for new appetite-controlling signals. Nesfatin-1 is the cleavage product of the calcium and DNA-binding protein nucleobindin2 (NUCB2),

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“…For induction of polymicrobial sepsis, mice were subjected to a CLP as described previously (21,22). In brief, a laparotomy was performed, and the cecum was isolated, ligated below the ileocecal valve, and punctured through and through with a 23-gauge needle.…”

Section: Cecal Ligation and Puncturementioning

confidence: 99%

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

Scumpia¹,

Delano²,

Kelly³

et al. 2006

The Journal of Immunology

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120

100

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Regulatory T cells (Tregs), including natural CD4+CD25+ Tregs and inducible IL-10 producing T regulatory type 1 (TR1) cells, maintain tolerance and inhibit autoimmunity. Recently, increased percentages of Tregs have been observed in the blood of septic patients, and ex vivo-activated Tregs were shown to prevent polymicrobial sepsis mortality. Whether endogenous Tregs contribute to sepsis outcome remains unclear. Polymicrobial sepsis, induced by cecal ligation and puncture, caused an increased number of splenic Tregs compared with sham-treated mice. Splenic CD4+CD25+ T cells from septic mice expressed higher levels of Foxp3 mRNA and were more efficient suppressors of CD4+CD25− T effector cell proliferation. Isolated CD4+ T cells from septic mice displayed increased intracellular IL-10 staining following stimulation, indicating that TR1 cells may also be elevated in sepsis. Surprisingly, Ab depletion of total CD4+ or CD4+CD25+ populations did not affect mortality. Furthermore, no difference in survival outcome was found between CD25 or IL-10 null mice and wild-type littermates, indicating that Treg or TR1-generated IL-10 are not required for survival. These results demonstrate that, although sepsis causes a relative increase in Treg number and increases their suppressive function, their presence does not contribute significantly to overall survival in this model.

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Increased Survival in Sepsis by In Vivo Adenovirus-Induced Expression of IL-10 in Dendritic Cells

Cited by 53 publications

References 36 publications

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

CD11c+ Dendritic Cells Are Required for Survival in Murine Polymicrobial Sepsis

Hypothalamic Nesfatin-1/NUCB2 Knockdown Augments Hepatic Gluconeogenesis That Is Correlated With Inhibition of mTOR-STAT3 Signaling Pathway in Rats

Increased Natural CD4+CD25+ Regulatory T Cells and Their Suppressor Activity Do Not Contribute to Mortality in Murine Polymicrobial Sepsis

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