Inhibition of the Defense System Stimulating Interleukin-12 Interferon-γ Pathway During Critical Illness

Abstract Interleukin-12 (IL-12) and interferon-γ (IFN-γ) exert protective effects during experimental endotoxemia through upregulation of cellular immunity and phagocytic functions. They are part of a positive regulatory feedback loop that enhances the production of the other. Because critically ill patients show a marked suppression of T-cell and macrophage functions with a high susceptibility to infection, potential defects in the immunity/inflammation upregulating IL-12 IFN-γ pathway were studied. As an ex vivo model of endotoxemia, lipopolysaccharide (LPS) stimulated whole blood from 25 critically ill patients and 12 healthy individuals was incubated with either recombinant human (rh) IL-12 or rhIFN-γ, respectively. IFN-γ dose-dependently (P < .05) increased the release of IL-12 p40 and p70 into LPS-stimulated whole blood from healthy humans without effect in whole blood from critically ill patients. RhIL-12 p70 enhanced (P < .05) the secretion of IFN-γ in controls, while it was ineffective in LPS-stimulated whole blood from critically ill patients. The observed inhibition of the IL-12 IFN-γ pathway is not specific to LPS, since Staphylococcus aureus Cowan strain I (SAC)-stimulated whole blood from critically ill patients showed similar suppression. The secretion of IL-12 and IFN-γ was less reduced in critically ill patients when using isolated cultures of adherent cells or lymphocytes. Although preculture of whole blood from healthy humans with IL-10, but not with IL-4, mimicked suppression of the IL-12 IFN-γ pathway similar to that observed during critical illness, the release of antiinflammatory reacting cytokines (IL-4, IL-10, transforming growth factor [TGF]-β1 ) was decreased into LPS-stimulated whole blood from critically ill patients. These results indicate at least two mechanisms responsible for dramatic disturbances of the IL-12 IFN-γ pathway during critical illness: (1) deactivation of IL-12 and IFN-γ producing leukocytes in vivo early after the primary insult, and (2) presence of serum suppressive factors different from IL-4, IL-10, or TGF-β1 . Because IL-12 and IFN-γ upregulate essential immune functions, the marked inhibition of IL-12 and IFN-γ release may be pivotal for high susceptibility of critically ill patients to infection.

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Inhibition of the Defense System Stimulating Interleukin-12 Interferon-γ Pathway During Critical Illness

Blood ◽

10.1182/blood.v89.5.1612.1612_1612_1620 ◽

1997 ◽

Vol 89 (5) ◽

pp. 1612-1620 ◽

Cited By ~ 1

Author(s):

Wolfgang Ertel ◽

Marius Keel ◽

Regula Neidhardt ◽

Ursula Steckholzer ◽

Jean-Pierre Kremer ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Whole Blood ◽

Interferon Γ ◽

Interleukin 12 ◽

High Susceptibility ◽

Healthy Humans ◽

Ifn Γ ◽

Tgf Β1

Interleukin-12 (IL-12) and interferon-γ (IFN-γ) exert protective effects during experimental endotoxemia through upregulation of cellular immunity and phagocytic functions. They are part of a positive regulatory feedback loop that enhances the production of the other. Because critically ill patients show a marked suppression of T-cell and macrophage functions with a high susceptibility to infection, potential defects in the immunity/inflammation upregulating IL-12 IFN-γ pathway were studied. As an ex vivo model of endotoxemia, lipopolysaccharide (LPS) stimulated whole blood from 25 critically ill patients and 12 healthy individuals was incubated with either recombinant human (rh) IL-12 or rhIFN-γ, respectively. IFN-γ dose-dependently (P < .05) increased the release of IL-12 p40 and p70 into LPS-stimulated whole blood from healthy humans without effect in whole blood from critically ill patients. RhIL-12 p70 enhanced (P < .05) the secretion of IFN-γ in controls, while it was ineffective in LPS-stimulated whole blood from critically ill patients. The observed inhibition of the IL-12 IFN-γ pathway is not specific to LPS, since Staphylococcus aureus Cowan strain I (SAC)-stimulated whole blood from critically ill patients showed similar suppression. The secretion of IL-12 and IFN-γ was less reduced in critically ill patients when using isolated cultures of adherent cells or lymphocytes. Although preculture of whole blood from healthy humans with IL-10, but not with IL-4, mimicked suppression of the IL-12 IFN-γ pathway similar to that observed during critical illness, the release of antiinflammatory reacting cytokines (IL-4, IL-10, transforming growth factor [TGF]-β1 ) was decreased into LPS-stimulated whole blood from critically ill patients. These results indicate at least two mechanisms responsible for dramatic disturbances of the IL-12 IFN-γ pathway during critical illness: (1) deactivation of IL-12 and IFN-γ producing leukocytes in vivo early after the primary insult, and (2) presence of serum suppressive factors different from IL-4, IL-10, or TGF-β1 . Because IL-12 and IFN-γ upregulate essential immune functions, the marked inhibition of IL-12 and IFN-γ release may be pivotal for high susceptibility of critically ill patients to infection.

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Identification of Cytokines in Whole Blood for Differential Diagnosis of Tuberculosis versus Pneumonia

Clinical and Vaccine Immunology ◽

10.1128/cvi.00526-09 ◽

2010 ◽

Vol 17 (5) ◽

pp. 771-777 ◽

Cited By ~ 5

Author(s):

Wen-Lin Su ◽

Wann-Cherng Perng ◽

Ching-Hui Huang ◽

Cheng-Yu Yang ◽

Chin-Pyng Wu ◽

...

Keyword(s):

Whole Blood ◽

Blood Cells ◽

Cutoff Point ◽

Interleukin 12 ◽

Operating Characteristics ◽

Percent Change ◽

Ifn Γ ◽

Sensitivity Specificity ◽

Whole Blood Cells ◽

Stimulation Of

ABSTRACT Differentiating tuberculosis (TB) from pneumonia remains a challenge. We evaluated the cytokine profiles of whole blood cells from patients with TB (n = 38) or pneumonia (n = 30) and from healthy individuals (n = 30) before and after stimulating cells with ESAT-6 or lipopolysaccharide (LPS). When the percent change in the levels of gamma interferon (IFN-γ) after stimulation with ESAT-6 was used in receiver operating characteristics (ROC) analysis (a graphic method to determine the diagnostic accuracy of a test) to identify a patient with TB, the area under the curve (AUC) was 90.4%, and a cutoff point of a 3.59% change produced a corresponding sensitivity, specificity, and accuracy of over 80%. When the change in IFN-γ after stimulation of blood cells with LPS was used to identify a patient with pneumonia, the AUC reached 89.1%, and a cutoff point of 3.59% produced a sensitivity, specificity, and accuracy of approximately 80% each. When the change in interleukin-12 (IL-12) after stimulation of blood cells with LPS was selected to define a patient with pneumonia, the AUC was 85.2%, and a cutoff point of 2.08% gave a sensitivity, specificity, and accuracy of 80.0%, 78.9%, and 79.4%, respectively. We conclude that the percent change in IFN-γ after stimulation of whole blood cells with ESAT-6 may differentiate patients with TB from patients with pneumonia. The percent change in IFN-γ and IL-12 after LPS stimulation of whole blood cells could differentiate patients with pneumonia from patients with TB.

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Critical Illness Outcomes Study: An Observational Cohort Of Critically Ill Patients

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a6788 ◽

2012 ◽

Author(s):

Jonathan E. Sevransky ◽

William Checkley ◽

Timothy D. Girard ◽

Steven M. Pastores ◽

Sajid Shahul ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Observational Cohort ◽

Outcomes Study ◽

Illness Outcomes

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Acute Respiratory Distress Syndrome and Time to Weaning Off the Invasive Mechanical Ventilator among Patients with COVID-19 Pneumonia

Journal of Clinical Medicine ◽

10.3390/jcm10132935 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2935

Author(s):

Jose Bordon ◽

Ozan Akca ◽

Stephen Furmanek ◽

Rodrigo Silva Cavallazzi ◽

Sally Suliman ◽

...

Keyword(s):

Acute Respiratory Distress Syndrome ◽

Critical Illness ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Critically Ill ◽

Critically Ill Patients ◽

Distress Syndrome ◽

Invasive Mechanical Ventilation ◽

Overall Mortality

Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) pneumonia is the main cause of the pandemic’s death toll. The assessment of ARDS and time on invasive mechanical ventilation (IMV) could enhance the characterization of outcomes and management of this condition. This is a city-wide retrospective study of hospitalized patients with COVID-19 pneumonia from 5 March 2020 to 30 June 2020. Patients with critical illness were compared with those with non-critical illness. We examined the severity of ARDS and other factors associated with (i) weaning patients off IMV and (ii) mortality in a city-wide study in Louisville, KY. Of 522 patients with COVID-19 pneumonia, 219 (41.9%) were critically ill. Among critically ill patients, the median age was 60 years; 53% were male, 55% were White and 32% were African American. Of all critically ill patients, 52% had ARDS, and 38% of these had severe ARDS. Of the 25% of patients who were weaned off IMV, those with severe ARDS were weaned within eleven days versus five days for those without severe ARDS, p = 0.023. The overall mortality for critically ill patients was 22% versus 1% for those not critically ill. Furthermore, the 14-day mortality was 31% for patients with severe ARDS and 12% for patients without severe ARDS, p = 0.019. Patients with severe ARDS versus non-severe ARDS needed twice as long to wean off IMV (eleven versus five days) and had double the 14-day mortality of patients without severe ARDS.

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Brain Death-Induced Inflammatory Activity is Similar to Sepsis-Induced Cytokine Release

Cell Transplantation ◽

10.1177/0963689718785629 ◽

2018 ◽

Vol 27 (10) ◽

pp. 1417-1424 ◽

Cited By ~ 2

Author(s):

Patrícia Schwarz ◽

Geisiane Custódio ◽

Jakeline Rheinheimer ◽

Daisy Crispim ◽

Cristiane B. Leitão ◽

...

Keyword(s):

Brain Death ◽

Critically Ill ◽

Critically Ill Patients ◽

Release Kinetics ◽

Magnetic Bead ◽

Control Group ◽

Cytokine Release ◽

Plasma Cytokine ◽

Ifn Γ ◽

Brain Dead

Brain death (BD) is associated with a systemic inflammation leading to worse graft outcomes. This study aimed to compare plasma cytokine values between brain-dead and critically ill patients, including septic and non-septic controls, and evaluate cytokine release kinetics in BD. Sixteen brain-dead and 32 control patients (16 with and 16 without sepsis) were included. Plasma cytokines were measured by magnetic bead assay after the first clinical exam consistent with BD and every 6 hours thereafter, and at the time of study entry in the control group. The values for IL-8 and IFN-γ were higher in brain-dead and septic patients than in non-septic patients [IL-8: 80.3 (18.7–169.6) vs. 68.2 (22.4–359.4) vs. 16.4 (9.2–42.7) pg/mL; P = 0.006; IFN-γ: 2.8 (1.6-6.1) vs. 3.4 (1.2–9.0) vs. 0.5 (0.5–1.8) pg/mL; P = 0.012]. TNF showed a clear tendency to increase in brain-dead patients [2.7 (1.0–4.8) vs. 1.0 (1.0–5.6) vs. 1.0 (1.0–1.0) pg/mL; P = 0.051], and IL-6 values were higher in brain-dead patients than in non-septic controls [174.5 (104.9–692.5) vs. 13.2 (7.3–38.6) pg/mL; P = 0.002]. These differences remained even after excluding brain-dead patients who also had sepsis ( n = 3). IL-1β and IL-10 values increased from baseline to time point 2 (∼6 hours later) [IL-1β: 5.39 (1.93–16.89) vs. 7.11 (1.93–29.13) pg/mL; P = 0.012; IL-10: 8.78 (3.62–16.49) vs. 15.73 (5.49–23.98) pg/mL; P = 0.009]. BD-induced and sepsis-induced plasma cytokine values were similarly high, and both were higher than the observed in non-septic critically ill patients.

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Regulation and Prognostic Relevance of Symmetric Dimethylarginine Serum Concentrations in Critical Illness and Sepsis

Mediators of Inflammation ◽

10.1155/2013/413826 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Alexander Koch ◽

Ralf Weiskirchen ◽

Jan Bruensing ◽

Hanna Dückers ◽

Lukas Buendgens ◽

...

Keyword(s):

Critical Illness ◽

Critically Ill ◽

Critically Ill Patients ◽

Multiorgan Failure ◽

Microvascular Dysfunction ◽

Serum Levels ◽

Serum Concentrations ◽

Symmetric Dimethylarginine ◽

Term Survival ◽

Severity Scores

In systemic inflammation and sepsis, endothelial activation and microvascular dysfunction are characteristic features that promote multiorgan failure. As symmetric dimethylarginine (SDMA) impacts vascular tension and integrity via modulating nitric oxide (NO) pathways, we investigated circulating SDMA in critical illness and sepsis. 247 critically ill patients (160 with sepsis, 87 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU) and on day 7, in comparison to 84 healthy controls. SDMA serum levels were significantly elevated in critically ill patients at admission to ICU compared to controls and remained stably elevated during the first week of ICU treatment. The highest SDMA levels were found in patients with sepsis. SDMA levels closely correlated with disease severity scores, biomarkers of inflammation, and organ failure (renal, hepatic, and circulatory). We identified SDMA serum concentrations at admission as an independent prognostic biomarker in critically ill patients not only for short-term mortality at the ICU but also for unfavourable long-term survival. Thus, the significant increase of circulating SDMA in critically ill patients indicates a potential pathogenic involvement in endothelial dysfunction during sepsis and may be useful for mortality risk stratification at the ICU.

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Role of Vitamin D in Premature Atherosclerosis in Adolescents Type 1 Diabetes through Transforming Growth Factor-β1, Interferon-γ, Interleukin-10, and Interleukin-17

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2020.4619 ◽

2020 ◽

Vol 8 (B) ◽

pp. 738-746

Author(s):

Haryudi Aji Cahyono ◽

Wisnu Barlianto ◽

Dian Handayani ◽

Handono Kalim

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Transforming Growth Factor ◽

Interleukin 10 ◽

Interferon Γ ◽

Transforming Growth Factor Β1 ◽

Premature Atherosclerosis ◽

Ifn Γ ◽

Tgf Β1

BACKGROUND: Cardiovascular disease (CVD) is one the cause of mortality in patients with type 1 diabetes (T1D). The development of CVD is mainly triggered by atherosclerosis, which is associated with the inflammatory process. AIM: The current study was aimed to investigate the association of Vitamin D level and premature atherosclerosis in adolescents with T1D, mainly through the regulation of various cytokines (interferon-γ [IFN-γ], IL-17, interleukin-10 [IL-10], and transforming growth factor-β1 [TGF-β1]). METHODS: This study was designed as a cross-sectional study involving 40 T1D and 40 healthy control who came to the outpatient clinic, Saiful Anwar Hospital, Malang, Indonesia, within the study period (January 2019-July 2019). RESULTS: Our data demonstrated that the IFN-γ and IL-17 levels were significantly higher (p < 0.001), whereas the TGF-β1 and IL-10 levels were significantly lower (p < 0.001) in T1D group compared with control. Furthermore, T1D also has higher carotid intima-media thickness (cIMT) value and lower flow-mediated dilatation (FMD) value compared to the control group (p < 0.001). Level of 25(OH)D3 was strongly associated with reduced cIMT and elevated FMD (p < 0.005). The direct effect of 25(OH)D3 on cIMT and FMD was higher than the indirect effect of Vitamin D through TGF-β1, IL-10, IL-17, and IFN-γ. The cutoff value of 25(OH)D3 levels for the risk of atherosclerosis was 12.8 ng/dL (sensitivity 85.7% and specificity 86.7%). CONCLUSION: The level of Vitamin D in the T1D group was significantly lower than those in healthy children and Vitamin D deficiency substantially influences the formation of premature atherosclerosis.

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Hemodialysis-Related Lymphomononuclear Release of Interleukin-12 in Patients with End-Stage Renal Disease

Journal of the American Society of Nephrology ◽

10.1681/asn.v10102171 ◽

1999 ◽

Vol 10 (10) ◽

pp. 2171-2176 ◽

Cited By ~ 1

Author(s):

BRUNO MEMOLI ◽

LUIGI MARZANO ◽

VINCENZO BISESTI ◽

MICHELE ANDREUCCI ◽

BRUNA GUIDA

Keyword(s):

Mononuclear Cells ◽

Interferon Γ ◽

Interleukin 12 ◽

Control Group ◽

Peripheral Blood Mononuclear ◽

Mitogen Stimulation ◽

Ifn Γ ◽

Uremic Patients ◽

Stage Renal Disease ◽

End Stage

Abstract. Interleukin-12 (IL-12) is a cytokine produced by peripheral blood mononuclear cells (PBMC) that causes interferon-γ (IFN-γ) production and enhancement of cell-mediated cytotoxicity. To clarify the role of hemodialysis biocompatibility on IL-12 production and uremic immunodeficiency, we have studied the IL-12 and IFN-γ release by PBMC harvested from 12 patients dialyzed with cuprophan membrane (CU), eight patients dialyzed with polymethylmethacrylate membrane (PMMA), and eight nondialyzed uremic patients (UR). Ten healthy subjects constituted the control group (CON). PBMC were cultured for 48 h with and without nonspecific mitogen stimulation. In unstimulated conditions, CU showed an IL-12 PBMC production higher than CON, UR, and PMMA (46.67 ± 30.13versus2.56 ± 1.38, 6.16 ± 7.09, and 4.62 ± 4.76 pg/ml, respectively;P< 0.01). IL-12 production was correlated with C3a concentration measured at the outlet of hemodialyzer after 15 min of dialysis (r= 0.69,P< 0.01). IL-12 release in CU remained unchanged under mitogen stimulation (44.34 ± 23.86 pg/ml) and was lower than in CON, UR, and PMMA (66.0 ± 12.41, 68.37 ± 25.78, and 67.75 ± 22.61 pg/ml, respectively;P< 0.05). IFN-γ production was similar, in unstimulated conditions, in all groups. Under stimulation, IFN-γ release was lower in CU (13.42 ± 12.04 IU/ml) than in CON, UR, and PMMA (51.84 ± 30.74, 32.16 ± 13.86, and 32.16 ± 13.86 IU/ml, respectively;P< 0.01). These results demonstrate that hemodialysis with CU induces monocyte activation with an enhanced release of IL-12. On the contrary, stimulated PBMC production of both IL-12 and IFN-γ is lower in these patients than in CON, UR, and PMMA. The altered release of these cytokines could play a role in cell-mediated immunodeficiency of the uremic patients dialyzed with CU.

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Critically Ill vs. Non-Critically Ill Patients With COVID-19 Pneumonia: Clinical Features, Laboratory Findings, and Prediction

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.550456 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wandong Hong ◽

Qin Chen ◽

Songzan Qian ◽

Zarrin Basharat ◽

Vincent Zimmer ◽

...

Keyword(s):

Critical Illness ◽

Disease Severity ◽

Critically Ill ◽

Clinical Features ◽

Critically Ill Patients ◽

Interleukin 6 ◽

Discharge Rate ◽

Laboratory Data ◽

Laboratory Findings ◽

Laboratory Parameters

ObjectivesThe objective of this study was to investigate the clinical features and laboratory findings of patients with and without critical COVID-19 pneumonia and identify predictors for the critical form of the disease.MethodsDemographic, clinical, and laboratory data of 63 COVID-19 pneumonia patients were retrospectively reviewed. Laboratory parameters were also collected within 3–5 days, 7–9 days, and 11–14 days of hospitalization. Outcomes were followed up until March 12, 2020.ResultsTwenty-two patients developed critically ill pneumonia; one of them died. Upon admission, older patients with critical illness were more likely to report cough and dyspnoea with higher respiration rates and had a greater possibility of abnormal laboratory parameters than patients without critical illness. When compared with the non-critically ill patients, patients with serious illness had a lower discharge rate and longer hospital stays, with a trend towards higher mortality. The interleukin-6 level in patients upon hospital admission was important in predicting disease severity and was associated with the length of hospitalization.ConclusionsMany differences in clinical features and laboratory findings were observed between patients exhibiting non-critically ill and critically ill COVID-19 pneumonia. Non-critically ill COVID-19 pneumonia also needs aggressive treatments. Interleukin-6 was a superior predictor of disease severity.

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