Reduced release of TNFα and IP-10 after ex vivo blood stimulation with endotoxin is associated with poor outcome after stroke

Klimiec, Elzbieta; Kowalska, Katarzyna; Pasińska, Paulina; Pera, Joanna; Słowik, Agnieszka; Dziedzic, Tomasz

doi:10.1016/j.cyto.2017.12.015

Cited by 11 publications

(15 citation statements)

References 27 publications

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“…Proinflammatory cytokines have long been suggested to contribute to ischemic injury owing to their roles in inducing the infiltration of inflammatory cells and accelerating the pathological process of ischemic stroke. Attenuated levels of proinflammatory cytokines may be associated with poor outcome after stroke [33,34]. In the present study, HMGB1, TLR4, NF-κB proteins, and inflammatory factors, including TNF-α, IL-1β, and IL-6, were all upregulated in the vehicle group compared with those in the sham group.…”

Section: Discussionsupporting

confidence: 49%

Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation

Zhu

Guo

et al. 2018

Acta Pharmacol Sin

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Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Berberine is a natural medicine with multiple beneficial biological activities. In this study, we explored the mechanisms underlying the neuroprotective action of berberine in mice subjected transient middle cerebral artery occlusion (tMCAO). Male mice were administered berberine (25, 50 mg/kg/d, intragastric; i.g.), glycyrrhizin (50 mg/kg/d, intraperitoneal), or berberine (50 mg/ kg/d, i.g.) plus glycyrrhizin (50 mg/kg/d, intraperitoneal) for 14 consecutive days before tMCAO. The neurological deficit scores were evaluated at 24 h after tMCAO, and then the mice were killed to obtain the brain samples. We showed that pretreatment with berberine dose-dependently decreased the infarct size, neurological deficits, hispathological changes, brain edema, and inflammatory mediators in serum and ischemic cortical tissue. We revealed that pretreatment with berberine significantly enhanced uptake of 18 F-fluorodeoxyglucose of ischemic hemisphere comparing with the vehicle group at 24 h after stroke. Furthermore, pretreatment with berberine dose-dependently suppressed the nuclear-to cytosolic translocation of high-mobility group box1 (HMGB1) protein, the cytosolic-to nuclear translocation of nuclear factor kappa B (NF-κB) and decreased the expression of TLR4 in ischemic cortical tissue. Moreover, co-administration of glycyrrhizin and berberine exerted more potent suppression on the HMGB1/TLR4/NF-κB pathway than berberine or glycyrrhizin administered alone. These results demonstrate that berberine protects the brain from ischemia-reperfusion injury and the mechanism may rely on its anti-inflammatory effects mediated by suppressing the activation of HMGB1/TLR4/NF-κB signaling.

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Section: Discussionsupporting

confidence: 49%

Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation

Zhu

Guo

et al. 2018

Acta Pharmacol Sin

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“…As expected, monocyte counts were positively correlated with Uninhibited TNF‐α (ie, the top of the dose‐response curve) because this value represents the production of TNF‐α in the absence of the inhibitory influence of dexamethasone. Prior ex vivo studies often express TNF‐α as a ratio per the number of monocytes, implying that monocytes are the sole source of ex vivo production of TNF‐α and that there is a direct one‐to‐one relationship between TNF production and monocyte number 39‐41 . However, in African American women's early pregnancy, we found that the number of monocytes could only explain 14% of the interindividual variation in TNF‐α production in the absence of glucocorticoids to suppress the immune response.…”

Section: Discussionmentioning

confidence: 63%

Glucocorticoid receptor sensitivity in early pregnancy in an African American cohort

Clarke

Corwin

Dunlop

et al. 2020

American J Rep Immunol

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Problem Disruption in homeostatic feedback loops between inflammatory mediators and the hypothalamic‐pituitary‐adrenal (HPA) axis is a key mechanism linking chronic stress to inflammation and adverse health outcomes, including those occurring during pregnancy. In particular, alterations in glucocorticoid sensitivity may occur as a result of chronic stress, including that due to racial discrimination, and may be implicated in the persistent adverse maternal and infant health outcomes experienced by African Americans. While there are a few large‐scale studies in human pregnancy that measure both cytokines and HPA axis hormones, to our knowledge, none directly measure glucocorticoid sensitivity at the cellular level, especially in an African American population. Method of study We measured the full range of the dexamethasone (DEX) dose‐response suppression of TNF‐α in first‐trimester blood samples from 408 African American women and estimated leukocyte cell type contribution to the production of TNF‐α. Results The mean (SD) DEX level needed to inhibit TNF‐α production by 50% (ie, DEX IC50) was 9.8 (5.8) nmol/L. Monocytes appeared to be the main driver of Uninhibited TNF‐α production, but monocyte counts explained only 14% of the variation. Monocyte counts were only weakly correlated with the DEX IC50 (r = −.11, P < .05). Moreover, there was no statistically significant correlation between the DEX IC50 and circulating pro‐inflammatory (CRP, IL‐6, IFN‐γ) or anti‐inflammatory (IL‐10) mediators (P > .05). Conclusion These findings challenge some prior assumptions and position this comprehensive study of glucocorticoid sensitivity as an important anchor point in the growing recognition of interindividual variation in maternal HPA axis regulation and inflammatory responses.

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“…They found the decreased TNFα, IL-1β, and IL-6 production after in vitro blood stimulation in non-survivors and patients with poor functional outcome. Recently, we reported that the reduced release of TNFα and IP-10 is independently from age and stroke severity associated with worse prognosis after stroke [9].…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, we diluted the whole blood by 1:5 in sterile RPMI 1640 medium supplemented with L-glutamine (Sigma Aldrich, St. Louis, MO, USA) and we stimulated it in sterile tubes (Lonza, Walkersville, MD, USA) with lipopolysaccharide (LPS 10 ng/mL, E. coli 0111:B4, Sigma Aldrich, St. Louis, MO, USA) at 37°C and 5% CO2. Based on previous publications [9,15], we stimulated blood for 4 h for TNFα and IP-10 and 24 h for interleukin IL-1β, IL-6, IL-8, IL-10, and IL-12p70. We removed supernatants and stored them at − 80°C.…”

Section: Laboratory Assaysmentioning

confidence: 99%

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The specific ex vivo released cytokine profile is associated with ischemic stroke outcome and improves its prediction

Klimiec-Moskal

Piechota

Pera

et al. 2020

J Neuroinflammation

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Background: Inflammation is associated with poor outcome after stroke. A relationship between ex vivo cytokine synthesis and stroke outcome remains unclear. We explored an association between ex vivo cytokine release, circulating interleukin (IL)-6 as a marker of systemic inflammation, and stroke prognosis. We assessed the utility of ex vivo synthesized cytokines for predicting stroke outcome. Methods: We collected blood from 248 ischemic stroke patients and stimulated it ex vivo with lipopolysaccharide. We measured concentration of synthesized cytokines (TNFα, IP-10, IL-1β, IL-6, IL-8, IL-10, and IL-12) and plasma IL-6. We assessed functional outcome 3 months after stroke using the modified Rankin Scale. To assess the prognostic ability of cytokines, we applied multivariate logistic regression, cluster analysis, and construction of multimarker score. Results: Decreased release of IP-10, TNFα, IL-1β, and IL-12; increased release of IL-10 and IL-8; and higher plasma IL-6 level were associated with poor outcome. Cluster analysis identified three groups of patients with distinct cytokine profiles. The group with the worst outcome demonstrated high synthesis of IL-10, IL-8, IL-1β, and IL-6 and low synthesis of IL-12, IP-10, and TNFα accompanied by high circulating IL-6 level. The group with the best prognosis showed high synthesis of TNFα, IP-10, IL-12, IL-1β, and IL-6; low synthesis of IL-10 and IL-8; and low plasma IL-6. Patients with intermediate outcome had low synthesis of all cytokines accompanied by low circulating IL-6. We constructed a multimarker score composed of ex vivo released IL-12, IL-10, TNFα, and plasma IL-6. Addition of this score to clinical variables led to significant increase in c-statistic (0.81 vs 0.73, p = 0.02) and net reclassification improvement. Conclusion: The decreased ex vivo release of pro-inflammatory cytokines and increased release of IL-10 and IL-8 are related to poor outcome after stroke. Cytokine-based multimarker score adds prognostic value to clinical model for predicting stroke outcome.

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Reduced release of TNFα and IP-10 after ex vivo blood stimulation with endotoxin is associated with poor outcome after stroke

Cited by 11 publications

References 27 publications

Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation

Berberine attenuates ischemia–reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation

Glucocorticoid receptor sensitivity in early pregnancy in an African American cohort

The specific ex vivo released cytokine profile is associated with ischemic stroke outcome and improves its prediction

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