Defining the proinflammatory phenotype using high sensitive C-reactive protein levels as the biomarker

Sridevi Devaraj, Grant O'Keefe, Ishwarlal Jialal

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Context: Inflammation is pivotal in atherosclerosis. The prototypic marker of inflammation is C-reactive protein (CRP). Numerous studies have confirmed that high CRP levels in normal volunteers predict cardiovascular events. Objective: The objective of this study was to define proximal and associated abnormalities of the proinflammatory phenotype using CRP levels as the biomarker. Design and Subjects: Two groups of normal, healthy subjects, selected by stringent criteria from an initial cohort of 252, were studied over the period of 12 months. Group 1 included subjects with consistently low CRP (<0.004 μM or <0.5 mg/liter; low CRP group; n = 15). Group 2 included subjects with consistently high CRP(>2.0 or >0.016 μM to <10 mg/liter or <0.085 μM; high CRP group; n = 13). Main Outcome Measures: Fasting blood (50 ml) was obtained, and the following parameters were assayed: high sensitivityCRP, fibrinogen, lipid profile, insulin, whole blood cytokines after stimulation with lipopolysaccharide (LPS; 100 ng/ml for 24 h), soluble cell adhesion molecules, plasminogen activator inhibitor-1, CD40, CD40 ligand, leptin, adiponectin, monocyte chemoattractant protein-1, IL-8, matrix metalloproteinase-3 (MMP-3), and MMP-9. Genomic DNA was obtained from peripheral blood leukocytes, and the TNF-α -308 genotype was determined. Results: The median CRP levels were 0.0018 μM (0.21 mg/liter) and 0.031 μM (3.7 mg/liter) for the low and high groups, respectively. High CRP subjects were older and had significantly higher body mass indexes, triglycerides, insulin, homeostasis model assessment, and leptin levels compared with low CRP subjects. The markers of inflammation, plasminogen activator inhibitor-1, MMP-9, fibrinogen, and vascular cell adhesion molecule-1 levels were significantly higher in the high compared with the low CRP group. LPS-stimulated levels of whole blood IL-1β, IL-6, and TNF were significantly higher, and IL-4 levels were significantly lower in the high CRP group. After ageand body mass index-adjusted analysis of covariance, only plasma MMP-9 levels and LPS-stimulated whole blood IL-1β and TNF levels were significantly higher in the high CRP group. The frequency of the rare A allele at TNF-α -308 was equivalent in high and low CRP groups. Conclusions: A phenotype characterized by increased plasma inflammatory mediators as well as increased LPS-stimulated whole blood TNF-α and IL-1β levels is associated with high plasma CRP levels. This systemic inflammatory phenotype may contribute to vascular inflammation or may reflect inflammation in vessels or at other sites.

Original languageEnglish (US)
Pages (from-to)4549-4554
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number8
DOIs
StatePublished - Aug 2005

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Biomarkers
C-Reactive Protein
Phenotype
Blood
Inflammation
Matrix Metalloproteinases
Interleukin-1
Plasminogen Activator Inhibitor 1
Leptin
Plasmas
Fibrinogen
Healthy Volunteers
Body Mass Index
Insulin
Matrix Metalloproteinase 3
CD40 Ligand
Vascular Cell Adhesion Molecule-1
Chemokine CCL2
Adiponectin
Cell Adhesion Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Defining the proinflammatory phenotype using high sensitive C-reactive protein levels as the biomarker. / Devaraj, Sridevi; O'Keefe, Grant; Jialal, Ishwarlal.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 8, 08.2005, p. 4549-4554.

Research output: Contribution to journalArticle

Devaraj, Sridevi ; O'Keefe, Grant ; Jialal, Ishwarlal. / Defining the proinflammatory phenotype using high sensitive C-reactive protein levels as the biomarker. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 8. pp. 4549-4554.
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abstract = "Context: Inflammation is pivotal in atherosclerosis. The prototypic marker of inflammation is C-reactive protein (CRP). Numerous studies have confirmed that high CRP levels in normal volunteers predict cardiovascular events. Objective: The objective of this study was to define proximal and associated abnormalities of the proinflammatory phenotype using CRP levels as the biomarker. Design and Subjects: Two groups of normal, healthy subjects, selected by stringent criteria from an initial cohort of 252, were studied over the period of 12 months. Group 1 included subjects with consistently low CRP (<0.004 μM or <0.5 mg/liter; low CRP group; n = 15). Group 2 included subjects with consistently high CRP(>2.0 or >0.016 μM to <10 mg/liter or <0.085 μM; high CRP group; n = 13). Main Outcome Measures: Fasting blood (50 ml) was obtained, and the following parameters were assayed: high sensitivityCRP, fibrinogen, lipid profile, insulin, whole blood cytokines after stimulation with lipopolysaccharide (LPS; 100 ng/ml for 24 h), soluble cell adhesion molecules, plasminogen activator inhibitor-1, CD40, CD40 ligand, leptin, adiponectin, monocyte chemoattractant protein-1, IL-8, matrix metalloproteinase-3 (MMP-3), and MMP-9. Genomic DNA was obtained from peripheral blood leukocytes, and the TNF-α -308 genotype was determined. Results: The median CRP levels were 0.0018 μM (0.21 mg/liter) and 0.031 μM (3.7 mg/liter) for the low and high groups, respectively. High CRP subjects were older and had significantly higher body mass indexes, triglycerides, insulin, homeostasis model assessment, and leptin levels compared with low CRP subjects. The markers of inflammation, plasminogen activator inhibitor-1, MMP-9, fibrinogen, and vascular cell adhesion molecule-1 levels were significantly higher in the high compared with the low CRP group. LPS-stimulated levels of whole blood IL-1β, IL-6, and TNF were significantly higher, and IL-4 levels were significantly lower in the high CRP group. After ageand body mass index-adjusted analysis of covariance, only plasma MMP-9 levels and LPS-stimulated whole blood IL-1β and TNF levels were significantly higher in the high CRP group. The frequency of the rare A allele at TNF-α -308 was equivalent in high and low CRP groups. Conclusions: A phenotype characterized by increased plasma inflammatory mediators as well as increased LPS-stimulated whole blood TNF-α and IL-1β levels is associated with high plasma CRP levels. This systemic inflammatory phenotype may contribute to vascular inflammation or may reflect inflammation in vessels or at other sites.",
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N2 - Context: Inflammation is pivotal in atherosclerosis. The prototypic marker of inflammation is C-reactive protein (CRP). Numerous studies have confirmed that high CRP levels in normal volunteers predict cardiovascular events. Objective: The objective of this study was to define proximal and associated abnormalities of the proinflammatory phenotype using CRP levels as the biomarker. Design and Subjects: Two groups of normal, healthy subjects, selected by stringent criteria from an initial cohort of 252, were studied over the period of 12 months. Group 1 included subjects with consistently low CRP (<0.004 μM or <0.5 mg/liter; low CRP group; n = 15). Group 2 included subjects with consistently high CRP(>2.0 or >0.016 μM to <10 mg/liter or <0.085 μM; high CRP group; n = 13). Main Outcome Measures: Fasting blood (50 ml) was obtained, and the following parameters were assayed: high sensitivityCRP, fibrinogen, lipid profile, insulin, whole blood cytokines after stimulation with lipopolysaccharide (LPS; 100 ng/ml for 24 h), soluble cell adhesion molecules, plasminogen activator inhibitor-1, CD40, CD40 ligand, leptin, adiponectin, monocyte chemoattractant protein-1, IL-8, matrix metalloproteinase-3 (MMP-3), and MMP-9. Genomic DNA was obtained from peripheral blood leukocytes, and the TNF-α -308 genotype was determined. Results: The median CRP levels were 0.0018 μM (0.21 mg/liter) and 0.031 μM (3.7 mg/liter) for the low and high groups, respectively. High CRP subjects were older and had significantly higher body mass indexes, triglycerides, insulin, homeostasis model assessment, and leptin levels compared with low CRP subjects. The markers of inflammation, plasminogen activator inhibitor-1, MMP-9, fibrinogen, and vascular cell adhesion molecule-1 levels were significantly higher in the high compared with the low CRP group. LPS-stimulated levels of whole blood IL-1β, IL-6, and TNF were significantly higher, and IL-4 levels were significantly lower in the high CRP group. After ageand body mass index-adjusted analysis of covariance, only plasma MMP-9 levels and LPS-stimulated whole blood IL-1β and TNF levels were significantly higher in the high CRP group. The frequency of the rare A allele at TNF-α -308 was equivalent in high and low CRP groups. Conclusions: A phenotype characterized by increased plasma inflammatory mediators as well as increased LPS-stimulated whole blood TNF-α and IL-1β levels is associated with high plasma CRP levels. This systemic inflammatory phenotype may contribute to vascular inflammation or may reflect inflammation in vessels or at other sites.

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