PMID- 25303153
OWN - NLM
STAT- MEDLINE
DCOM- 20150629
LR  - 20220408
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 10
DP  - 2014
TI  - The role of TLR2 and 4-mediated inflammatory pathways in endothelial cells 
      exposed to high glucose.
PG  - e108844
LID - 10.1371/journal.pone.0108844 [doi]
LID - e108844
AB  - Postprandial hyperglycemia induces inflammation and endothelial dysfunction 
      resulting in vascular complications in patients with diabetes. Toll-like 
      receptors (TLRs) are central to the regulation of inflammatory responses through 
      activation of nuclear factor-kappa B (NF-kB). This study examined the role of 
      TLR2 and 4 in regulating inflammation and endothelial dysfunction when exposed to 
      fluctuating glucose concentrations. HMEC-1 cells (a human microvascular 
      endothelial cell line) were exposed to control (5 mM), 30 mM (high), fluctuating 
      (5/30 mM) and 11.2 mM glucose (approximate glycaemic criteria for the diagnosis 
      of diabetes mellitus) for 72 h. Cells were assessed for TLR2, 4, high mobility 
      group box -1 (HMGB1), NF-kB, monocyte chemoattractant protein-1 (MCP-1), 
      interleukin-8 (IL-8), intercellular adhesion molecule-1 (ICAM-1) and vascular 
      cell adhesion molecule-1 (VCAM-1). Fluctuating glucose concentrations maximally 
      upregulated TLR4 but not TLR2 expression with increased NF-kB activation, IL-8 
      and ICAM-1 expression. HMGB1 was increased in the supernatants of cells exposed 
      to 30 mM and 11.2 mM glucose compared to control. The addition of recombinant 
      HMGB1 induced NF-kB activation and synthesis of proinflammatory cytokines and 
      chemokines, which were prevented by TLR2 or 4 signalling inhibition. An additive 
      effect when both TLR2 and 4 signalling pathways were inhibited was observed. 
      However, only inhibition of TLR4 signalling suppressed the synthesis of MCP-1, 
      IL-8 and ICAM-1. In vivo, streptozotocin-induced diabetic mice exhibited an 
      increase in glomerular ICAM-1 which was not evident in TLR2(-/-) or TLR4(-/-) 
      diabetic mice. Collectively, our results suggest that targeting the signalling 
      pathway of TLR2 and 4 may be of therapeutic benefit in attenuating vascular 
      inflammation in diabetic microangiopathy.
FAU - Mudaliar, Harshini
AU  - Mudaliar H
AD  - Renal Research Group, Kolling Institute of Medical Research, University of 
      Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
FAU - Pollock, Carol
AU  - Pollock C
AD  - Renal Research Group, Kolling Institute of Medical Research, University of 
      Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
FAU - Ma, Jin
AU  - Ma J
AD  - Renal Medicine Royal Prince Alfred Hospital and Collaborative Transplant Research 
      Group, University of Sydney, Camperdown, New South Wales, Australia.
FAU - Wu, Huiling
AU  - Wu H
AD  - Renal Medicine Royal Prince Alfred Hospital and Collaborative Transplant Research 
      Group, University of Sydney, Camperdown, New South Wales, Australia.
FAU - Chadban, Steven
AU  - Chadban S
AD  - Renal Medicine Royal Prince Alfred Hospital and Collaborative Transplant Research 
      Group, University of Sydney, Camperdown, New South Wales, Australia.
FAU - Panchapakesan, Usha
AU  - Panchapakesan U
AD  - Renal Research Group, Kolling Institute of Medical Research, University of 
      Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141010
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Diabetes Mellitus, Experimental/genetics/*immunology/pathology
MH  - Endothelial Cells/*immunology/pathology
MH  - Gene Deletion
MH  - Glucose/*immunology
MH  - Humans
MH  - Inflammation/genetics/immunology/pathology
MH  - Intercellular Adhesion Molecule-1/immunology
MH  - Mice, Inbred BALB C
MH  - Signal Transduction
MH  - Toll-Like Receptor 2/genetics/*immunology
MH  - Toll-Like Receptor 4/genetics/*immunology
PMC - PMC4193767
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/10/11 06:00
MHDA- 2015/06/30 06:00
PMCR- 2014/10/10
CRDT- 2014/10/11 06:00
PHST- 2014/04/29 00:00 [received]
PHST- 2014/09/05 00:00 [accepted]
PHST- 2014/10/11 06:00 [entrez]
PHST- 2014/10/11 06:00 [pubmed]
PHST- 2015/06/30 06:00 [medline]
PHST- 2014/10/10 00:00 [pmc-release]
AID - PONE-D-14-19298 [pii]
AID - 10.1371/journal.pone.0108844 [doi]
PST - epublish
SO  - PLoS One. 2014 Oct 10;9(10):e108844. doi: 10.1371/journal.pone.0108844. 
      eCollection 2014.