Global Effect of Interleukin-10 on the Transcriptional Profile Induced by Neisseria meningitidis in Human Monocytes

Gopinathan, Unni; Øvstebø, Reidun; Olstad, Ole Kristoffer; Brusletto, Berit; Aass, Hans Christian Dalsbotten; Kierulf, Peter; Brandtzæg, Petter; Berg, Jens Petter

doi:10.1128/iai.00386-12

Cited by 18 publications

(37 citation statements)

References 57 publications

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“…However, consistent with previous findings, the IL-10 effect was most prominent in repression of LPS-induced inflammatory genes (Gopinathan et al, 2012;Lang et al, 2002a;Murray, 2005), possibly through epigenetic mechanisms Kobayashi et al, 2012;Simon et al, 2016). In addition, IL-10 also induced expression of LPS-repressed genes including those related to carbohydrate and lipid metabolism, in line with a recent report that the anti-inflammatory effects of IL-10 involve metabolic reprogramming of Mφs (Ip et al, 2017).…”

Section: Discussionsupporting

confidence: 91%

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

Mukhopadhyay

Heinz

Porreca

et al. 2019

Journal of Experimental Medicine

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Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells (iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL-10RB−/− iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS induced inflammatory cytokines in the presence of exogenous IL-10. IL-10RB−/− Mφs exhibited a striking defect in their ability to kill Salmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RB gene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced in IL-10RB−/− Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls. Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs. These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφ activation and impaired host defense contributing to IBD pathogenesis.

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Section: Discussionsupporting

confidence: 91%

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

Mukhopadhyay

Heinz

Porreca

et al. 2019

Journal of Experimental Medicine

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“…We suggest our in vitro patient plasma model more closely reflects the gene expression changes that occur during the initial stage of severe human endotoxemia than previously published studies. [18][19][20][21][22] Thus, we believe that the present study adds knowledge to how the intense pro-and antiinflammatory responses in a septic patient may alter gene expression. However, our data are descriptive, and future studies should investigate the functional significance suggested by these gene expression findings.…”

Section: Resultsmentioning

confidence: 96%

IL-10 immunodepletion from meningococcal sepsis plasma induces extensive changes in gene expression and cytokine release in stimulated human monocytes

et al. 2014

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The severity of systemic meningococcal disease (SMD) correlates to plasma concentrations of LPS and IL-10, with the highest levels detected in non-survivors. Here, plasma from patients with SMD containing high and low concentrations of LPS were incubated with human monocytes before and after immunodepletion of IL-10 to study the effect of IL-10 on gene expression and cytokine release. Patient plasma containing IL-10 induced the expression of 1657 genes in human monocytes when compared with gene expression induced by low LPS plasma. After immunodepletion of IL-10, this number increased to 2260. By directly comparing the gene expression profiles induced before and after immunodepletion of IL-10, the presence of IL-10 differentially regulated 373 genes. Functional classes associated with these genes were cellular function and maintenance, cellular development, cellular growth and proliferation, cell-cell signaling and interaction and cellular movement. Immunodepletion of IL-10 resulted in down-regulation of genes of the leukocyte immunoglobulin-like receptor family, and up-regulation of genes of type I IFN signaling, TLR signaling, the inflammasomes, coagulation and fibrinolysis. Finally, immunodepletion of IL-10 increased the protein levels of IL-1β, IL-8, TNF-α, MIP-1α and MIP-1β. Data suggest that IL-10 in meningococcal sepsis plasma regulates a variety of genes and signaling pathways, likely leading to an overall inhibitory effect on the inflammatory response induced in meningococcal sepsis.

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“…Nm-infected human monocytes produce high levels of pro-inflammatory cytokines (TNF-a, IL-6 and IL-8). These levels were reduced by 36-58% when IL-10 was given with infecting meningococci [27]. Beneficial effect of IL-10 on sepsis mortality in mice have already been described [28][29][30] but these early beneficial effects are counterbalanced by secondary pejorative effects of those anti-inflammatory cytokines in sepsis.…”

Section: Discussionmentioning

confidence: 94%

Impact of corticosteroids on experimental meningococcal sepsis in mice

et al. 2015

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Neisseria meningitidis is responsible for septicemia and meningitis with high fatality that is associated with an excessive inflammatory reaction particularly with hyperinvasive isolates of the clonal complex ST-11 (cc11). However, anti-inflammatory adjuvant treatment remains controversial and difficult to assess in patients. We addressed this topic in a well-defined experimental meningococcal infection in transgenic mice expressing the human transferrin. Mice were infected by intra-peritoneal challenge with bioluminescent serogroup C/cc11 strain. After 3h of infection mice were differentially treated every 6h by saline, amoxicillin alone or amoxicillin and dexamethasone (DXM). Infected mice were scored for clinical status, temperature and weight. Biological markers of inflammation were also quantified. Significant clinical improvement was observed in mice treated with amoxicillin and DXM compared to the two other groups. A significant reduction of the inflammatory reaction assessed by CRP and Lipocalin 2 (two acute phase proteins) was also observed with this treatment. DXM significantly increased blood levels of IL-10 at 6h post-infection. DXM/amoxicillin treated mice, compared to the two other groups, also showed lower levels of TNF-α and lower bacterial blood load assessed by serial dilutions of blood and bioluminescence dynamic imaging. Our results suggest that DXM, added to an appropriate antibiotic therapy, has a beneficial effect on experimental sepsis with a hyperinvasive meningococcal strain in transgenic mice expressing human transferrin. This is most likely due to the reduction of inflammatory response by an early induction of IL-10 cytokine. These data may allow better decision-making to use or not corticotherapy during meningococcal sepsis.

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Global Effect of Interleukin-10 on the Transcriptional Profile Induced by Neisseria meningitidis in Human Monocytes

Cited by 18 publications

References 57 publications

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2

IL-10 immunodepletion from meningococcal sepsis plasma induces extensive changes in gene expression and cytokine release in stimulated human monocytes

Impact of corticosteroids on experimental meningococcal sepsis in mice

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