Lipopolysaccharide-induced production of interleukin-10 is promoted by the serine/threonine kinase Akt

Pengal, Ruma A.; Ganesan, Latha P.; Guo, Wei; Fang, Huiqing; Ostrowski, Michael C.; Tridandapani, Susheela

doi:10.1016/j.molimm.2005.09.022

Cited by 108 publications

(92 citation statements)

References 41 publications

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“…Further investigations with mice carrying a targeted disruption of the catalytic p110 component in cells of myeloid origin should clarify this discrepancy. However, increased resistance to VSV infection was also observed when cells were harvested from transgenic mice overexpressing a mutated (constitutively active) form of the Akt kinase in cells of myeloid origin (data not shown) (Pengal et al, 2006). Altogether, these genetic data confirm the positive effect of PI3K activation on viral resistance in macrophages and extend our results obtained with pharmacological impairment of this pathway.…”

Section: Discussionsupporting

confidence: 80%

TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages

Schabbauer

Luyendyk

Crozat

et al. 2008

Molecular Immunology

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Phosphatidylinositol-3-phosphate kinase (PI3K) has been reported to exhibit anti-inflammatory roles as a negative modulator of the NF-κB pathway (MyD88-and Mal-dependent) triggered upon Tolllike receptor (TLR)4 activation by lipopolysaccharide (LPS). Here, we investigated the role of PI3K on the TLR4-dependent, MyD88-independent signaling cascade which is activated in macrophages infected by Vesicular Stomatitis Virus (VSV) and leads to interferon production, thus conferring antiviral protection. We show that VSV induces TLR4 (and CD14)-dependent Akt phosphorylation. We observed hypersusceptibility to viral infections after pharmacological inactivation of the PI3K pathway in macrophages, which indicates that normal PI3K functions are critical for type I interferon synthesis and viral resistance. Conversely, we noticed increased resistance in macrophages isolated from genetically modified mice in which the PI3K pathway is constitutively active. Our data, which demonstrate that PI3K-Akt axis is an important component of the TLR4-dependent antiviral mechanism, also indicate that pharmacological modulation of this pathway to regulate the inflammatory response could promote viral susceptibility.

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Section: Discussionsupporting

confidence: 80%

TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages

Schabbauer

Luyendyk

Crozat

et al. 2008

Molecular Immunology

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“…More precisely, we observed a correlation between IL-10 and the presence of T cells, although not specifically with T reg . A possible explanation for this observation could be that other cells, like M. tuberculosis-infected dendritic cells and macrophages, express IL-10, particularly in the presence of effector T cells (20,21). Despite significant differences in protection and T cell responses, histological analyses revealed similar granuloma shape, size, and numbers between infected C57BL/6 wt and T cellreconstituted Rag1…”

Section: Resultsmentioning

confidence: 96%

Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis

Kursar

Koch

Mittrücker

et al. 2007

The Journal of Immunology

252

190

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Mycobacterium tuberculosis remains one of the top microbial killers of humans causing ∼2 million deaths annually. More than 90% of the 2 billion individuals infected never develop active disease, indicating that the immune system is able to generate mechanisms that control infection. However, the immune response generally fails to achieve sterile clearance of bacilli. Using adoptive cell transfer into C57BL/6J-Rag1tm1Mom mice (Rag1−/−), we show that regulatory T cells prevent eradication of tubercle bacilli by suppressing an otherwise efficient CD4+ T cell response. This protective CD4+ T cell response was not correlated with increased numbers of IFN-γ- or TNF-α-expressing cells or general expression levels of IFN-γ or inducible NO synthase in infected organs compared with wild-type C57BL/6 animals. Furthermore, suppression of protection by cotransferred regulatory T cells was neither accompanied by a general increase of IL-10 expression nor by higher numbers of IL-10-producing CD4+ T cells.

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“…Other components of bacteria that may trigger IL-10 include LPS (79) and species-specific molecules such as M protein of Streptococcus pyogenes, which induces IL-10 via Tr1 cells (80). LPS triggers the production of IL-10 in noninfectious experimental models that incorporate dendritic cells and macrophage stimulation, for example (81,82). LPS also activates key innate immune mechanisms, including TLR-4, CD14, and NF-kB (83), which were shown to be activated by UPEC within the KEGG TLR signaling pathway and the strongly induced IPA network for IL-10 signaling.…”

Section: Discussionmentioning

confidence: 99%

Innate Transcriptional Networks Activated in Bladder in Response to Uropathogenic Escherichia coli Drive Diverse Biological Pathways and Rapid Synthesis of IL-10 for Defense against Bacterial Urinary Tract Infection

Duell

Carey

Tan

et al. 2012

The Journal of Immunology

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Early transcriptional activation events that occur in bladder immediately following bacterial urinary tract infection (UTI) are not well defined. In this study, we describe the whole bladder transcriptome of uropathogenic Escherichia coli (UPEC) cystitis in mice using genome-wide expression profiling to define the transcriptome of innate immune activation stemming from UPEC colonization of the bladder. Bladder RNA from female C57BL/6 mice, analyzed using 1.0 ST-Affymetrix microarrays, revealed extensive activation of diverse sets of innate immune response genes, including those that encode multiple IL-family members, receptors, metabolic regulators, MAPK activators, and lymphocyte signaling molecules. These were among 1564 genes differentially regulated at 2 h postinfection, highlighting a rapid and broad innate immune response to bladder colonization. Integrative systems-level analyses using InnateDB (http://www.innatedb.com) bioinformatics and ingenuity pathway analysis identified multiple distinct biological pathways in the bladder transcriptome with extensive involvement of lymphocyte signaling, cell cycle alterations, cytoskeletal, and metabolic changes. A key regulator of IL activity identified in the transcriptome was IL-10, which was analyzed functionally to reveal marked exacerbation of cystitis in IL-10–deficient mice. Studies of clinical UTI revealed significantly elevated urinary IL-10 in patients with UPEC cystitis, indicating a role for IL-10 in the innate response to human UTI. The whole bladder transcriptome presented in this work provides new insight into the diversity of innate factors that determine UTI on a genome-wide scale and will be valuable for further data mining. Identification of protective roles for other elements in the transcriptome will provide critical new insight into the complex cascade of events that underpin UTI.

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Lipopolysaccharide-induced production of interleukin-10 is promoted by the serine/threonine kinase Akt

Cited by 108 publications

References 41 publications

TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages

TLR4/CD14-mediated PI3K activation is an essential component of interferon-dependent VSV resistance in macrophages

Cutting Edge: Regulatory T Cells Prevent Efficient Clearance of Mycobacterium tuberculosis

Innate Transcriptional Networks Activated in Bladder in Response to Uropathogenic Escherichia coli Drive Diverse Biological Pathways and Rapid Synthesis of IL-10 for Defense against Bacterial Urinary Tract Infection

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