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TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase
Jie Fan, … , Randall S. Frey, Asrar B. Malik
Jie Fan, … , Randall S. Frey, Asrar B. Malik
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1234-1243. https://doi.org/10.1172/JCI18696.
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Article Aging

TLR4 signaling induces TLR2 expression in endothelial cells via neutrophil NADPH oxidase

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Abstract

Interactions of polymorphonuclear neutrophils (PMNs) with endothelial cells may contribute to the activation of endothelial cell responses involved in innate immunity. We explored a novel function of PMN NADPH oxidase in the mechanism of Toll-like receptor-2 (TLR2) upregulation induced by LPS-TLR4 signaling in endothelial cells. We showed that LPS induced TLR2 up-regulation through TLR4- and MyD88-dependent signaling. In neutropenic mice, the LPS-induced NF-kB activation and TLR2 expression were significantly reduced, and both responses were restored upon repletion by PMN obtained from WT mice but not by PMNs from NADPH oxidase gp91phox–/– mice. These findings were recapitulated in mouse lung vascular endothelial cells cocultured with PMNs, indicating that the augmented NF-kB activation and the resultant TLR2 upregulation in endothelial cells were secondary to oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in endothelial cells was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and peptidoglycan. Thus, PMN NADPH oxidase–derived oxidant signaling is an important determinant of the cross talk between TLR4 and TLR2 and the control of endothelial cell activation.

Authors

Jie Fan, Randall S. Frey, Asrar B. Malik

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Figure 1

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LPS upregulates TLR2 expression in lungs and endothelial cells through T...
LPS upregulates TLR2 expression in lungs and endothelial cells through TLR4 and MyD88 signaling. (a and b) Mice were injected intraperitoneally with LPS (10 μg/10 g body wt) and whole lungs were harvested at the times indicated after LPS injection. Data are representative of three independent studies. (a) RT-PCR for TLR2 mRNA expression in the lungs. GAPDH mRNA is identified as a control for RNA loading. (b) Western blot for TLR2 protein in lungs. Corresponding actin is shown as evidence of comparable loading between lanes. (c and d) MLVECs were incubated with LPS (1 μg/ml) for 2 hours, TLR2 mRNA was detected using RT-PCR (c), and TLR2 protein level was measured by Western blotting (d). The data are representative of three independent studies.

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