Insulin Increases the Release of Proinflammatory Mediators

Brundage, Susan I.; Kirilcuk, Natalie; Lam, Jason; Spain, David A.; Zautke, Nathan A.

doi:10.1097/ta.0b013e3181801cc0

Cited by 22 publications

(18 citation statements)

References 40 publications

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“…We next sought to investigate whether it also took place during endotoxin tolerance. Tolerant THP-1 cells show reduced glycolysis (Fig 2A-B) and serve as a model for septic shock (47-49). …”

Section: Resultsmentioning

confidence: 99%

GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism

Millet

Vachharajani

McPhail

et al. 2016

The Journal of Immunology

118

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Expression of the inflammatory cytokine TNF is tightly controlled. During endotoxin tolerance, transcription of TNF mRNA is repressed, although not entirely eliminated. Production of TNF cytokine, however, is further controlled by post-transcriptional regulation. In this study, we detail a mechanism of post-transcriptional repression of TNF mRNA by GAPDH binding to the TNF 3’UTR. Using RNA immunoprecipitation, we demonstrate that GAPDH-TNF mRNA binding increases when THP-1 monocytes are in a low glycolysis state, and that this binding can be reversed by knocking down GAPDH expression or by increasing glycolysis. We show that reducing glycolysis decreases TNF mRNA association with polysomes. We demonstrate that GAPDH-TNF mRNA binding results in post-transcriptional repression of TNF and that the TNF mRNA 3’UTR is sufficient for repression. Finally, after exploring this model in THP-1 cells, we demonstrate this mechanism affects TNF expression in primary human monocytes and macrophages. We conclude that GAPDH-TNF mRNA binding regulates expression of TNF based on cellular metabolic state. We believe this mechanism has potentially significant implications for treatment of various immunometabolic conditions, including immune paralysis during septic shock.

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Section: Resultsmentioning

confidence: 99%

GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism

Millet

Vachharajani

McPhail

et al. 2016

The Journal of Immunology

118

View full text Add to dashboard Cite

show abstract

“…For example, T2DM is a disease characterized by chronic hyperglycemia owing to the reduced sensitivity of cells to insulin. The continuous dysregulation of plasma glucose levels generates an environment of chronic inflammation through means of increased levels of circulating pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and advanced glycation end products (AGEs), as well as oxidative stress (Brundage et al, 2008;Iida et al, 2001;Nowotny et al, 2015). In addition to increasing muscle sensitivity to insulin (Holloszy, 2005), PA also reduces the pro-inflammatory environment in T2DM patients, as demonstrated by a reduction in the cellular markers of inflammation ICAM1 and CRP (Falconer et al, 2014;Zoppini et al, 2006).…”

Section: Physical Activity and Exercise As An Intervention For Periphmentioning

confidence: 99%

Physical activity and exercise attenuate neuroinflammation in neurological diseases

Spielman

Little

Klegeris

2016

Brain Research Bulletin

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“…As far as therapy is concerned, despite the increased use of insulin drips and the higher number of glucose checks after adopting a stricter insulin treatment protocol, ICU outcomes remained unchanged [40]. In an experimental model of activated macrophages [41], insulin does not prove to have direct anti-inflammatory properties.…”

Section: Prevalence and Prognostic Value Of Hyperglycemiamentioning

confidence: 99%

Glucose dysmetabolism and prognosis in critical illness

et al. 2008

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Acute hyperglycemia frequently present in stress conditions, has long been generally accepted as normal, and not thought to be a cause for concern since a moderate hyperglycemia in critically ill adult patients has been thought to be beneficial during the "fight or flight" response to ensure a supply of glucose as a source of energy to organs that do not require insulin for glucose uptake (i.e., the brain and the immune system). However, an increasing body of evidence associates the upon-admission degree and duration of hyperglycemia during critical illness with an adverse outcome. Hyperglycemia should be regarded as a part of the systemic and complex metabolic derangements observed in critical illness in response to stress and inflammation, which can lead, independent of initial disease, to multiorgan dysfunction and death. A tight glycemic control should be constantly pursued and achieved by insulin infusion bearing in mind that the therapeutic target is fighting the systemic inflammatory response and not merely the glucose plasma levels.

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Insulin Increases the Release of Proinflammatory Mediators

Abstract: Contrary to our hypothesis, insulin does not have direct anti-inflammatory properties in this experimental model. In fact, insulin increases proinflammatory cytokine protein levels from activated macrophages.

Cited by 22 publications

References 40 publications

GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism

GAPDH Binding to TNF-α mRNA Contributes to Posttranscriptional Repression in Monocytes: A Novel Mechanism of Communication between Inflammation and Metabolism

Physical activity and exercise attenuate neuroinflammation in neurological diseases

Glucose dysmetabolism and prognosis in critical illness

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