TY - JOUR
T1 - Circulating pathogen associated molecular pattern-binding proteins and high mobility group box protein 1 in nascent metabolic syndrome
T2 - Implications for cellular toll-like receptor activity
AU - Jialal, I.
AU - Rajamani, U.
AU - Adams-Huet, B.
AU - Kaur, H.
N1 - Funding Information:
The study was supported by grant from American Diabetes Association (to I.J.).
PY - 2014/9
Y1 - 2014/9
N2 - Objective: The Metabolic Syndrome, (MetS) a global epidemic, is a state of low grade chronic inflammation and confers an increased risk for diabetes and CVD. We have previously reported increased activity of the pathogen recognition receptors, Toll-like receptors (TLRs), TLR2 and TLR4 in MetS. We hypothesized that increased TLR activity in MetS is due in part to increased levels of circulating PAMP-binding proteins, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP) and the damage associated molecular pattern (DAMP), High Mobility Group Box protein 1 (HMGB-1). Methods: We measured sCD14, LBP and HMGB-1 in fasting plasma from nascent MetS (n=37) and healthy control subjects (n=32) by ELISA. We also investigated the effects of sCD14 and LBP on TLR4 activity in human aortic endothelial cells (HAECs). Results: Following adjustment for body mass index and waist circumference, sCD14, LBP and HMGB-1 levels remained significantly increased in MetS. Also their levels increased with increasing numbers of MetS risk factors. Only sCD14 correlated significantly with monocyte TLR4 protein and activity. None of these soluble biomarkers correlated with TLR2 protein. Both sCD14 and HMGB-1 correlated significantly with HOMA-IR.In LPS primed HAECs, sCD14 compared to LBP, resulted in a greater increase in both TLR4 abundance and inflammatory biomediators (NF-κB, IL-1β, IL-8 and TNF-α). Conclusion: Thus, we make the novel observation that sCD14 reflects increased monocyte TLR4 protein and activity in nascent MetS and by contributing to increased cellular inflammation could explain, in part, the increased risk for diabetes and CVD.
AB - Objective: The Metabolic Syndrome, (MetS) a global epidemic, is a state of low grade chronic inflammation and confers an increased risk for diabetes and CVD. We have previously reported increased activity of the pathogen recognition receptors, Toll-like receptors (TLRs), TLR2 and TLR4 in MetS. We hypothesized that increased TLR activity in MetS is due in part to increased levels of circulating PAMP-binding proteins, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP) and the damage associated molecular pattern (DAMP), High Mobility Group Box protein 1 (HMGB-1). Methods: We measured sCD14, LBP and HMGB-1 in fasting plasma from nascent MetS (n=37) and healthy control subjects (n=32) by ELISA. We also investigated the effects of sCD14 and LBP on TLR4 activity in human aortic endothelial cells (HAECs). Results: Following adjustment for body mass index and waist circumference, sCD14, LBP and HMGB-1 levels remained significantly increased in MetS. Also their levels increased with increasing numbers of MetS risk factors. Only sCD14 correlated significantly with monocyte TLR4 protein and activity. None of these soluble biomarkers correlated with TLR2 protein. Both sCD14 and HMGB-1 correlated significantly with HOMA-IR.In LPS primed HAECs, sCD14 compared to LBP, resulted in a greater increase in both TLR4 abundance and inflammatory biomediators (NF-κB, IL-1β, IL-8 and TNF-α). Conclusion: Thus, we make the novel observation that sCD14 reflects increased monocyte TLR4 protein and activity in nascent MetS and by contributing to increased cellular inflammation could explain, in part, the increased risk for diabetes and CVD.
KW - HMGB-1
KW - Metabolic syndrome
KW - PAMP-binding proteins
KW - SCD14
KW - Toll-like receptors
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U2 - 10.1016/j.atherosclerosis.2014.06.022
DO - 10.1016/j.atherosclerosis.2014.06.022
M3 - Article
C2 - 25063948
AN - SCOPUS:84905833861
SN - 0021-9150
VL - 236
SP - 182e187
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -