In vivo and ex vivo inflammatory markers of common metabolic phenotypes in humans

Rasmus Baadsgaard Mærkedahl; Hanne Frøkiær; Marie Grøntved Stenbæk; Camilla Betak Nielsen; Mads Vendelbo Lind; Christian Lundtoft; Marietta Boje Bohr; Sabine Ibrügger; Stine Broeng Metzdorff; Henrik Vestergaard; Oluf Borbye Pedersen; Lotte Lauritzen

doi:10.1089/met.2017.0121

In vivo and ex vivo inflammatory markers of common metabolic phenotypes in humans

Rasmus Baadsgaard Mærkedahl, Hanne Frøkiær^*, Marie Grøntved Stenbæk, Camilla Betak Nielsen, Mads Vendelbo Lind, Christian Lundtoft, Marietta Boje Bohr, Sabine Ibrügger, Stine Broeng Metzdorff, Henrik Vestergaard, Oluf Borbye Pedersen, Lotte Lauritzen

^*Corresponding author for this work

1 Citation (Scopus)

Abstract

Background: Low-grade systemic inflammation (LGSI) is often characterized by elevated levels of interleukin (IL)6, tumor necrosis factor (TNF)α, and C-reactive protein (CRP). Other serum proteins, ex vivo-stimulated cytokine production, and leukocyte count have, however, also been suggested LGSI-markers, but their associations with the metabolic syndrome (MS) are less clear. We aimed to evaluate mutual relationships between in vivo and ex vivo inflammatory markers and their association with MS and its subcomponents. Methods: A cross-sectional study of 118 overweight adults with one or several features of MS. Inflammatory markers included fasting serum levels of IL6, TNFα, CRP, and pentraxin-3 (PTX3), IL1-receptors, leukocytes, and whole-blood ex vivo-produced IL1β, IL6, TNFα, and IL8 after lipopolysaccharide stimulation. Results: All classical serum LGSI-markers correlated with each other, and IL6 and CRP were also correlated with leukocyte count. Ex vivo-produced cytokines were intercorrelated and correlated with leukocyte count, but did not correlate with the serum immune markers. MS score, body mass index, and glycated hemoglobin (HbA1c) were associated with 8%-16% higher inflammatory score per standard deviation increment (P = 0.030, 0.001, and 0.034, respectively), primarily driven by higher serum IL6. Serum PTX3 was only significantly associated with high-density lipoprotein cholesterol (1.19[1.04; 1.37], P = 0.013). HbA1c was inversely associated with surface expression of IL1R1 on monocytes and IL1R2 on granulocytes (P < 0.01) and with a 3%-9% lower ex vivo production of cytokines when adjusting for leukocyte count, as were plasma triacylglycerol (9%-10% lower IL1β and IL6). Leukocyte count was most consistently associated with MS and its subcomponents, although not with HbA1. Conclusions: The classical fasting serum markers of LGSI and leukocyte counts associated best with measures of MS-associated LGSI, whereas ex vivo cytokine production was only associated with prevailing glycemia and dyslipidemia. Taken together, this indicates that the relationship between in vivo and ex vivo inflammatory markers is complex and may depend on the MS phenotype.

Original language	English
Journal	Metabolic Syndrome and Related Disorders
Volume	16
Issue number	1
Pages (from-to)	29-39
Number of pages	11
ISSN	1540-4196
DOIs	https://doi.org/10.1089/met.2017.0121
Publication status	Published - Feb 2018

Keywords

Serum markers of inflammation
Stimulated ex vivo cytokine production
Leukocyte count
Insulin resistance
Dyslipidemia
Obesity

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10.1089/met.2017.0121

Cite this

Mærkedahl, R. B., Frøkiær, H., Stenbæk, M. G., Nielsen, C. B., Lind, M. V., Lundtoft, C., Bohr, M. B., Ibrügger, S., Metzdorff, S. B., Vestergaard, H., Pedersen, O. B., & Lauritzen, L. (2018). In vivo and ex vivo inflammatory markers of common metabolic phenotypes in humans. Metabolic Syndrome and Related Disorders, 16(1), 29-39. https://doi.org/10.1089/met.2017.0121

@article{849170212ac647cd87d3b48424cddb4a,

title = "In vivo and ex vivo inflammatory markers of common metabolic phenotypes in humans",

abstract = "Background: Low-grade systemic inflammation (LGSI) is often characterized by elevated levels of interleukin (IL)6, tumor necrosis factor (TNF)α, and C-reactive protein (CRP). Other serum proteins, ex vivo-stimulated cytokine production, and leukocyte count have, however, also been suggested LGSI-markers, but their associations with the metabolic syndrome (MS) are less clear. We aimed to evaluate mutual relationships between in vivo and ex vivo inflammatory markers and their association with MS and its subcomponents. Methods: A cross-sectional study of 118 overweight adults with one or several features of MS. Inflammatory markers included fasting serum levels of IL6, TNFα, CRP, and pentraxin-3 (PTX3), IL1-receptors, leukocytes, and whole-blood ex vivo-produced IL1β, IL6, TNFα, and IL8 after lipopolysaccharide stimulation. Results: All classical serum LGSI-markers correlated with each other, and IL6 and CRP were also correlated with leukocyte count. Ex vivo-produced cytokines were intercorrelated and correlated with leukocyte count, but did not correlate with the serum immune markers. MS score, body mass index, and glycated hemoglobin (HbA1c) were associated with 8%-16% higher inflammatory score per standard deviation increment (P = 0.030, 0.001, and 0.034, respectively), primarily driven by higher serum IL6. Serum PTX3 was only significantly associated with high-density lipoprotein cholesterol (1.19[1.04; 1.37], P = 0.013). HbA1c was inversely associated with surface expression of IL1R1 on monocytes and IL1R2 on granulocytes (P < 0.01) and with a 3%-9% lower ex vivo production of cytokines when adjusting for leukocyte count, as were plasma triacylglycerol (9%-10% lower IL1β and IL6). Leukocyte count was most consistently associated with MS and its subcomponents, although not with HbA1. Conclusions: The classical fasting serum markers of LGSI and leukocyte counts associated best with measures of MS-associated LGSI, whereas ex vivo cytokine production was only associated with prevailing glycemia and dyslipidemia. Taken together, this indicates that the relationship between in vivo and ex vivo inflammatory markers is complex and may depend on the MS phenotype.",

keywords = "Serum markers of inflammation, Stimulated ex vivo cytokine production, Leukocyte count, Insulin resistance, Dyslipidemia, Obesity",

author = "M{\ae}rkedahl, {Rasmus Baadsgaard} and Hanne Fr{\o}ki{\ae}r and Stenb{\ae}k, {Marie Gr{\o}ntved} and Nielsen, {Camilla Betak} and Lind, {Mads Vendelbo} and Christian Lundtoft and Bohr, {Marietta Boje} and Sabine Ibr{\"u}gger and Metzdorff, {Stine Broeng} and Henrik Vestergaard and Pedersen, {Oluf Borbye} and Lotte Lauritzen",

note = "CURIS 2018 NEXS 024",

year = "2018",

month = feb,

doi = "10.1089/met.2017.0121",

language = "English",

volume = "16",

pages = "29--39",

journal = "Metabolic Syndrome and Related Disorders",

issn = "1540-4196",

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TY - JOUR

T1 - In vivo and ex vivo inflammatory markers of common metabolic phenotypes in humans

AU - Mærkedahl, Rasmus Baadsgaard

AU - Frøkiær, Hanne

AU - Stenbæk, Marie Grøntved

AU - Nielsen, Camilla Betak

AU - Lind, Mads Vendelbo

AU - Lundtoft, Christian

AU - Bohr, Marietta Boje

AU - Ibrügger, Sabine

AU - Metzdorff, Stine Broeng

AU - Vestergaard, Henrik

AU - Pedersen, Oluf Borbye

AU - Lauritzen, Lotte

N1 - CURIS 2018 NEXS 024

PY - 2018/2

Y1 - 2018/2

N2 - Background: Low-grade systemic inflammation (LGSI) is often characterized by elevated levels of interleukin (IL)6, tumor necrosis factor (TNF)α, and C-reactive protein (CRP). Other serum proteins, ex vivo-stimulated cytokine production, and leukocyte count have, however, also been suggested LGSI-markers, but their associations with the metabolic syndrome (MS) are less clear. We aimed to evaluate mutual relationships between in vivo and ex vivo inflammatory markers and their association with MS and its subcomponents. Methods: A cross-sectional study of 118 overweight adults with one or several features of MS. Inflammatory markers included fasting serum levels of IL6, TNFα, CRP, and pentraxin-3 (PTX3), IL1-receptors, leukocytes, and whole-blood ex vivo-produced IL1β, IL6, TNFα, and IL8 after lipopolysaccharide stimulation. Results: All classical serum LGSI-markers correlated with each other, and IL6 and CRP were also correlated with leukocyte count. Ex vivo-produced cytokines were intercorrelated and correlated with leukocyte count, but did not correlate with the serum immune markers. MS score, body mass index, and glycated hemoglobin (HbA1c) were associated with 8%-16% higher inflammatory score per standard deviation increment (P = 0.030, 0.001, and 0.034, respectively), primarily driven by higher serum IL6. Serum PTX3 was only significantly associated with high-density lipoprotein cholesterol (1.19[1.04; 1.37], P = 0.013). HbA1c was inversely associated with surface expression of IL1R1 on monocytes and IL1R2 on granulocytes (P < 0.01) and with a 3%-9% lower ex vivo production of cytokines when adjusting for leukocyte count, as were plasma triacylglycerol (9%-10% lower IL1β and IL6). Leukocyte count was most consistently associated with MS and its subcomponents, although not with HbA1. Conclusions: The classical fasting serum markers of LGSI and leukocyte counts associated best with measures of MS-associated LGSI, whereas ex vivo cytokine production was only associated with prevailing glycemia and dyslipidemia. Taken together, this indicates that the relationship between in vivo and ex vivo inflammatory markers is complex and may depend on the MS phenotype.

AB - Background: Low-grade systemic inflammation (LGSI) is often characterized by elevated levels of interleukin (IL)6, tumor necrosis factor (TNF)α, and C-reactive protein (CRP). Other serum proteins, ex vivo-stimulated cytokine production, and leukocyte count have, however, also been suggested LGSI-markers, but their associations with the metabolic syndrome (MS) are less clear. We aimed to evaluate mutual relationships between in vivo and ex vivo inflammatory markers and their association with MS and its subcomponents. Methods: A cross-sectional study of 118 overweight adults with one or several features of MS. Inflammatory markers included fasting serum levels of IL6, TNFα, CRP, and pentraxin-3 (PTX3), IL1-receptors, leukocytes, and whole-blood ex vivo-produced IL1β, IL6, TNFα, and IL8 after lipopolysaccharide stimulation. Results: All classical serum LGSI-markers correlated with each other, and IL6 and CRP were also correlated with leukocyte count. Ex vivo-produced cytokines were intercorrelated and correlated with leukocyte count, but did not correlate with the serum immune markers. MS score, body mass index, and glycated hemoglobin (HbA1c) were associated with 8%-16% higher inflammatory score per standard deviation increment (P = 0.030, 0.001, and 0.034, respectively), primarily driven by higher serum IL6. Serum PTX3 was only significantly associated with high-density lipoprotein cholesterol (1.19[1.04; 1.37], P = 0.013). HbA1c was inversely associated with surface expression of IL1R1 on monocytes and IL1R2 on granulocytes (P < 0.01) and with a 3%-9% lower ex vivo production of cytokines when adjusting for leukocyte count, as were plasma triacylglycerol (9%-10% lower IL1β and IL6). Leukocyte count was most consistently associated with MS and its subcomponents, although not with HbA1. Conclusions: The classical fasting serum markers of LGSI and leukocyte counts associated best with measures of MS-associated LGSI, whereas ex vivo cytokine production was only associated with prevailing glycemia and dyslipidemia. Taken together, this indicates that the relationship between in vivo and ex vivo inflammatory markers is complex and may depend on the MS phenotype.

KW - Serum markers of inflammation

KW - Stimulated ex vivo cytokine production

KW - Leukocyte count

KW - Insulin resistance

KW - Dyslipidemia

KW - Obesity

U2 - 10.1089/met.2017.0121

DO - 10.1089/met.2017.0121

M3 - Journal article

C2 - 29319419

SN - 1540-4196

VL - 16

SP - 29

EP - 39

JO - Metabolic Syndrome and Related Disorders

JF - Metabolic Syndrome and Related Disorders

IS - 1