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Cross Tolerance and Potentiation of Toll‐like Receptors in Endothelial Cells
Author(s) -
Stark Ryan J,
Koch Stephen R,
Lamb Fred S,
Sherwood Edward R
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.957.4
Subject(s) - tlr4 , agonist , tlr2 , inflammation , lipopolysaccharide , receptor , toll like receptor , pharmacology , tlr3 , medicine , umbilical vein , immunology , chemistry , innate immune system , in vitro , biochemistry
Toll‐like receptors (TLR) are important regulators of inflammation in endothelial cells. Activation of TLRs can reduce the pro‐inflammatory response to a subsequent TLR challenge, inducing a state of “tolerance”. We hypothesized that activation of TLR2 and TLR3 would induce cross tolerance to TLR4 activation. We cultured human microvascular (HMVECs) and umbilical vein (HUVECs) endothelial cells and exposed them to the TLR4 agonist lipopolysaccharide (LPS), the TLR3 agonist poly I:C, or the TLR1/2 agonist Pam3CSK4 for 16 hours. Cells were washed and then allowed to rest in media for 30 hours. Afterwards, cells were re‐exposed to different TLR ligands for 16 hours. Inflammation was assessed by quantifying IL‐6 levels in the culture media. Initial LPS exposure rendered both HUVECs and HMVECs tolerant to subsequent LPS exposure with a 47% and 48% reduction in IL‐6, respectively (p <0.05). Contrary to this, initial exposure to poly I:C increased IL‐6 production after LPS re‐exposure compared to LPS alone by 25% in HMVECs and 35% in HUVECs (p <0.05). Interestingly, though Pam3CSK4 produced little IL‐6 in HMVECs compared HUVECs (11.18 pg/ml HMVECs vs. 2197 pg/ml in HUVECs), initial exposure of HMVECs to Pam3CSK4 reduced IL‐6 in cells re‐exposed to LPS by 43% compared to LPS alone(p <0.05). These studies provide new knowledge into the modulatory relationship between TLRs in inciting inflammation in endothelial cells. Support or Funding Information This work was supported by the National Institute of General Medical Sciences (K08‐GM117367, R.S., R01‐GM104306, E. S.)