Skip to main content
Top
Published in: BMC Immunology 1/2017

Open Access 01-12-2017 | Research article

Hyporesponsiveness of natural killer cells and impaired inflammatory responses in critically ill patients

Authors: Minkyung Kim, Minjoo Kim, Hana Jeong, Jey Sook Chae, Young Sam Kim, Jae Gil Lee, Younsoo Cho, Jong Ho Lee

Published in: BMC Immunology | Issue 1/2017

Login to get access

Abstract

Background

To investigate natural killer (NK) cell activity, circulating cytokine level and peripheral blood mononuclear cell (PBMC) cytokine production status in critically ill patients.

Methods

Blood samples were collected <24 h after admission from 24 intensive care unit (ICU) patients and 24 age-, sex-, and body mass index (BMI)-matched healthy controls. Serum cytokine concentrations and cytokine production by PBMCs and lipopolysaccharide (LPS)-stimulated PBMCs were measured.

Results

The ICU group showed lower NK cell activity than the controls under all conditions and an absence of interferon (IFN)-γ. After adjusting for triglycerides, LDL- and HDL-cholesterol, and glucose, the ICU group exhibited lower serum levels of albumin and interleukin (IL)-12 and higher leukocyte counts and hs-CRP and IL-6 levels than the controls. Non-stimulated PBMCs from ICU patients secreted significantly greater amounts of IL-6 and IL-1β than the controls; however, the production of IL-6, TNF-α and IL-1β in response to LPS stimulation was significantly lower in the ICU group.

Conclusions

Significant reductions in NK cell activity and serum IL-12 level, an absence of serum IFN-γ, and decreased cytokine production from LPS-stimulated PBMCs indicate the hyporesponsiveness of NK cells and an impaired early phase inflammatory response in critically ill patients (ClinicalTrials.gov NCT02565589:). Retrospectively registered; October 1, 2015.
Literature
1.
go back to reference Andaluz-Ojeda D, Iglesias V, Bobillo F, et al. Early levels in blood of immunoglobulin M and natural killer cells predict outcome in nonseptic critically ill patients. J Crit Care. 2013;28:1110.CrossRefPubMed Andaluz-Ojeda D, Iglesias V, Bobillo F, et al. Early levels in blood of immunoglobulin M and natural killer cells predict outcome in nonseptic critically ill patients. J Crit Care. 2013;28:1110.CrossRefPubMed
2.
go back to reference Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost. 2009;101:36–47.PubMed Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost. 2009;101:36–47.PubMed
3.
4.
go back to reference Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;29:617–25.CrossRefPubMedPubMedCentral Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;29:617–25.CrossRefPubMedPubMedCentral
5.
go back to reference Monneret G, Venet F, Kullberg BJ, Netea MG. ICU-acquired immunosuppression and the risk for secondary fungal infections. Med Mycol. 2011;49(Suppl 1):S17–23.CrossRefPubMed Monneret G, Venet F, Kullberg BJ, Netea MG. ICU-acquired immunosuppression and the risk for secondary fungal infections. Med Mycol. 2011;49(Suppl 1):S17–23.CrossRefPubMed
6.
go back to reference Opal SM. Immunologic alterations and the pathogenesis of organ failure in the ICU. Semin Respir Crit Care Med. 2011;32:569–80.CrossRefPubMed Opal SM. Immunologic alterations and the pathogenesis of organ failure in the ICU. Semin Respir Crit Care Med. 2011;32:569–80.CrossRefPubMed
7.
go back to reference Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008;29:605–16. viiCrossRefPubMed Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008;29:605–16. viiCrossRefPubMed
8.
go back to reference Spolarics Z, Siddiqi M, Siegel JH, et al. Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward Th2-type lymphocyte pattern in severely injured male trauma patients. Crit Care Med. 2003;31:1722–9.CrossRefPubMed Spolarics Z, Siddiqi M, Siegel JH, et al. Depressed interleukin-12-producing activity by monocytes correlates with adverse clinical course and a shift toward Th2-type lymphocyte pattern in severely injured male trauma patients. Crit Care Med. 2003;31:1722–9.CrossRefPubMed
9.
go back to reference Weighardt H, Heidecke CD, Westerholt A, et al. Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis. Ann Surg. 2002;235:560–7.CrossRefPubMedPubMedCentral Weighardt H, Heidecke CD, Westerholt A, et al. Impaired monocyte IL-12 production before surgery as a predictive factor for the lethal outcome of postoperative sepsis. Ann Surg. 2002;235:560–7.CrossRefPubMedPubMedCentral
10.
go back to reference Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M. Immunosuppression following surgical and traumatic injury. Surg Today. 2010;40:793–808.CrossRefPubMed Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M. Immunosuppression following surgical and traumatic injury. Surg Today. 2010;40:793–808.CrossRefPubMed
11.
go back to reference Wu HP, Shih CC, Chu CM, et al. Effect of interleukin-17 on in vitro cytokine production in healthy controls and patients with severe sepsis. J Formos Med Assoc. 2015;114:1250–7.CrossRefPubMed Wu HP, Shih CC, Chu CM, et al. Effect of interleukin-17 on in vitro cytokine production in healthy controls and patients with severe sepsis. J Formos Med Assoc. 2015;114:1250–7.CrossRefPubMed
12.
go back to reference Wu HP, Shih CC, Lin CY, Hua CC, Chuang DY. Serial increase of IL-12 response and human leukocyte antigen-DR expression in severe sepsis survivors. Crit Care. 2011;15:R224.CrossRefPubMedPubMedCentral Wu HP, Shih CC, Lin CY, Hua CC, Chuang DY. Serial increase of IL-12 response and human leukocyte antigen-DR expression in severe sepsis survivors. Crit Care. 2011;15:R224.CrossRefPubMedPubMedCentral
13.
go back to reference Hamers L, Kox M, Pickkers P. Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options. Minerva Anestesiol. 2015;81:426–39.PubMed Hamers L, Kox M, Pickkers P. Sepsis-induced immunoparalysis: mechanisms, markers, and treatment options. Minerva Anestesiol. 2015;81:426–39.PubMed
14.
go back to reference Drewry AM, Ablordeppey EA, Murray ET, et al. Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Crit Care. 2016;20:334.CrossRefPubMedPubMedCentral Drewry AM, Ablordeppey EA, Murray ET, et al. Comparison of monocyte human leukocyte antigen-DR expression and stimulated tumor necrosis factor alpha production as outcome predictors in severe sepsis: a prospective observational study. Crit Care. 2016;20:334.CrossRefPubMedPubMedCentral
15.
go back to reference Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37:525–32.CrossRefPubMed Hall MW, Knatz NL, Vetterly C, et al. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011;37:525–32.CrossRefPubMed
16.
go back to reference Hall MW, Geyer SM, Guo CY, et al. Innate immune function and mortality in critically ill children with influenza: a multicenter study. Crit Care Med. 2013;41:224–36.CrossRefPubMedPubMedCentral Hall MW, Geyer SM, Guo CY, et al. Innate immune function and mortality in critically ill children with influenza: a multicenter study. Crit Care Med. 2013;41:224–36.CrossRefPubMedPubMedCentral
17.
go back to reference Mandal A, Viswanathan C. Natural killer cells: in health and disease. Hematol Oncol Stem Cell Ther. 2015;8:47–55.CrossRefPubMed Mandal A, Viswanathan C. Natural killer cells: in health and disease. Hematol Oncol Stem Cell Ther. 2015;8:47–55.CrossRefPubMed
18.
go back to reference Huntington ND, Vosshenrich CA, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol. 2007;7:703–14.CrossRefPubMed Huntington ND, Vosshenrich CA, Di Santo JP. Developmental pathways that generate natural-killer-cell diversity in mice and humans. Nat Rev Immunol. 2007;7:703–14.CrossRefPubMed
19.
go back to reference Badgwell B, Parihar R, Magro C, Dierksheide J, Russo T, Carson WE 3rd. Natural killer cells contribute to the lethality of a murine model of Escherichia Coli infection. Surgery. 2002;132:205–12.CrossRefPubMed Badgwell B, Parihar R, Magro C, Dierksheide J, Russo T, Carson WE 3rd. Natural killer cells contribute to the lethality of a murine model of Escherichia Coli infection. Surgery. 2002;132:205–12.CrossRefPubMed
20.
go back to reference Etogo AO, Nunez J, Lin CY, Toliver-Kinsky TE, Sherwood ER. NK but not CD1-restricted NKT cells facilitate systemic inflammation during polymicrobial intra-abdominal sepsis. J Immunol. 2008;180:6334–45.CrossRefPubMedPubMedCentral Etogo AO, Nunez J, Lin CY, Toliver-Kinsky TE, Sherwood ER. NK but not CD1-restricted NKT cells facilitate systemic inflammation during polymicrobial intra-abdominal sepsis. J Immunol. 2008;180:6334–45.CrossRefPubMedPubMedCentral
21.
22.
go back to reference Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.CrossRefPubMed Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.CrossRefPubMed
23.
go back to reference Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858–73.CrossRefPubMed Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858–73.CrossRefPubMed
24.
go back to reference Dellinger RP, Levy MM, Carlet JM, et al. Surviving se psis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327.CrossRefPubMed Dellinger RP, Levy MM, Carlet JM, et al. Surviving se psis campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36:296–327.CrossRefPubMed
25.
go back to reference Lee JG, Kim YS, Lee YJ, et al. Effect of immune-enhancing Enteral nutrition enriched with or without Beta-Glucan on Immunomodulation in critically ill patients. Nutrients. 2016;8:336.CrossRefPubMedCentral Lee JG, Kim YS, Lee YJ, et al. Effect of immune-enhancing Enteral nutrition enriched with or without Beta-Glucan on Immunomodulation in critically ill patients. Nutrients. 2016;8:336.CrossRefPubMedCentral
26.
go back to reference Kjaergaard AG, Nielsen JS, Tønnesen E, Krog J. Expression of NK cell and monocyte receptors in critically ill patients--potential biomarkers of sepsis. Scand J Immunol. 2015;81:249–58.CrossRefPubMed Kjaergaard AG, Nielsen JS, Tønnesen E, Krog J. Expression of NK cell and monocyte receptors in critically ill patients--potential biomarkers of sepsis. Scand J Immunol. 2015;81:249–58.CrossRefPubMed
27.
go back to reference Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9.CrossRefPubMedPubMedCentral Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, Yokoyama WM, Ugolini S. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9.CrossRefPubMedPubMedCentral
28.
go back to reference Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–46.CrossRefPubMed Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–46.CrossRefPubMed
29.
go back to reference Stanilova SA, Karakolev ZT, Dimov GS, et al. High interleukin 12 and low interleukin 10 production after in vitro stimulation detected in sepsis survivors. Intensive Care Med. 2005;31:401–7.CrossRefPubMed Stanilova SA, Karakolev ZT, Dimov GS, et al. High interleukin 12 and low interleukin 10 production after in vitro stimulation detected in sepsis survivors. Intensive Care Med. 2005;31:401–7.CrossRefPubMed
30.
go back to reference Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36:1859–66.CrossRefPubMed Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36:1859–66.CrossRefPubMed
31.
go back to reference Calder PC, Jensen GL, Koletzko BV, Singer P, Wanten GJ. Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions. Intensive Care Med. 2010;36:735–49.CrossRefPubMedPubMedCentral Calder PC, Jensen GL, Koletzko BV, Singer P, Wanten GJ. Lipid emulsions in parenteral nutrition of intensive care patients: current thinking and future directions. Intensive Care Med. 2010;36:735–49.CrossRefPubMedPubMedCentral
32.
go back to reference Ott J, Hiesgen C, Mayer K. Lipids in critical care medicine. Prostaglandins Leukot Essent Fatty Acids. 2011;85:267–73.CrossRefPubMed Ott J, Hiesgen C, Mayer K. Lipids in critical care medicine. Prostaglandins Leukot Essent Fatty Acids. 2011;85:267–73.CrossRefPubMed
33.
go back to reference Barros KV, Cassulino AP, Schalch L, et al. Pharmaconutrition: acute fatty acid modulation of circulating cytokines in elderly patients in the ICU. JPEN J Parenter Enteral Nutr. 2014;38:467–74.CrossRefPubMed Barros KV, Cassulino AP, Schalch L, et al. Pharmaconutrition: acute fatty acid modulation of circulating cytokines in elderly patients in the ICU. JPEN J Parenter Enteral Nutr. 2014;38:467–74.CrossRefPubMed
34.
go back to reference Giger U, Büchler M, Farhadi J, et al. Preoperative immunonutrition suppresses perioperative inflammatory response in patients with major abdominal surgery-a randomized controlled pilot study. Ann Surg Oncol. 2007;14:2798–806.CrossRefPubMed Giger U, Büchler M, Farhadi J, et al. Preoperative immunonutrition suppresses perioperative inflammatory response in patients with major abdominal surgery-a randomized controlled pilot study. Ann Surg Oncol. 2007;14:2798–806.CrossRefPubMed
35.
37.
go back to reference Valente SA, Fallon WF Jr, Alexander TS, et al. Immunologic function in the elderly after injury--the neutrophil and innate immunity. J Trauma. 2009;67:968–74.CrossRefPubMed Valente SA, Fallon WF Jr, Alexander TS, et al. Immunologic function in the elderly after injury--the neutrophil and innate immunity. J Trauma. 2009;67:968–74.CrossRefPubMed
38.
go back to reference Brüünsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin N Am. 2003;23:15–39.CrossRef Brüünsgaard H, Pedersen BK. Age-related inflammatory cytokines and disease. Immunol Allergy Clin N Am. 2003;23:15–39.CrossRef
39.
go back to reference Gomez CR, Karavitis J, Palmer JL, et al. Interleukin-6 contributes to age-related alteration of cytokine production by macrophages. Mediat Inflamm. 2010;2010:475139.CrossRef Gomez CR, Karavitis J, Palmer JL, et al. Interleukin-6 contributes to age-related alteration of cytokine production by macrophages. Mediat Inflamm. 2010;2010:475139.CrossRef
40.
go back to reference Ottinger ME, Monaghan SF, Gravenstein S, Cioffi WG, Ayala A, Heffernan DS. The geriatric cytokine response to trauma: time to consider a new threshold. Surg Infect. 2014;15:800–5.CrossRef Ottinger ME, Monaghan SF, Gravenstein S, Cioffi WG, Ayala A, Heffernan DS. The geriatric cytokine response to trauma: time to consider a new threshold. Surg Infect. 2014;15:800–5.CrossRef
41.
go back to reference Jing Y, Shaheen E, Drake RR, Chen N, Gravenstein S, Deng Y. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol. 2009;70:777–84.CrossRefPubMedPubMedCentral Jing Y, Shaheen E, Drake RR, Chen N, Gravenstein S, Deng Y. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol. 2009;70:777–84.CrossRefPubMedPubMedCentral
Metadata
Title
Hyporesponsiveness of natural killer cells and impaired inflammatory responses in critically ill patients
Authors
Minkyung Kim
Minjoo Kim
Hana Jeong
Jey Sook Chae
Young Sam Kim
Jae Gil Lee
Younsoo Cho
Jong Ho Lee
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2017
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-017-0231-y

Other articles of this Issue 1/2017

BMC Immunology 1/2017 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.