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Tissue factor inflammatory response regulated by promoter genotype and p38 MAPK in neonatal vs. adult microvascular endothelial cells

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Abstract

Objective and design

Variable tissue factor (TF) expression by human microvascular endothelial cells (HMVEC) may be regulated by two promoter haplotypes, distinguished by an 18-basepair deletion (D) or insertion (I) at −1,208. We sought to determine the relationship between these haplotypes and interleukin-1α (IL-1α)-induced TF expression in neonatal versus adult HMVEC.

Results

IL-1-stimulated TF mRNA, protein, and activity were significantly higher in neonatal compared to adult D/D donors. IL-1-stimulated HMVEC from neonatal D/D donors expressed threefold higher levels of TF mRNA, twofold higher TF protein, and fourfold increased TF activity compared to HMVEC from adult D/D donors. These results indicate that homozygosity for the D haplotype is characterized by increased response to IL-1 in neonates, but not adults. IL-1 induced increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), which was significantly greater in neonatal compared to adult HMVEC. Moreover, inhibition of the p38 MAPK pathway reduced IL-1-stimulated TF mRNA expression in D/D neonatal but not adult HMVEC.

Conclusions

Upregulation of D/D neonatal HMVEC TF expression by IL-1 is mediated through the p38 MAPK pathway. This heightened response of D/D neonatal HMVEC to inflammatory stimuli may contribute to increased microvascular coagulopathies in susceptible newborn infants.

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Acknowledgments

This work was supported by grants from the CHOC Children’s Foundation (JSB) and Novo Nordisk A/S (JSB). TJK was funded by R01 HL086904 from the National heart, Lung and Blood Institute.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Hematology Research Laboratory, 510 Research Institute, CHOC Children’s Hospital of Orange County, 1201 W. La Veta Avenue, Orange, CA, 92868, USA

    Jeffrey S. Buzby, Shirley A. Williams, Thomas J. Kunicki & Diane J. Nugent

  2. Hematology Advanced Diagnostics Laboratory, 560 Research Institute, CHOC Children’s Hospital of Orange County, 1201 W. La Veta Avenue, Orange, CA, 92868, USA

    Jeffrey S. Buzby, Shirley A. Williams, Karen L. Imfeld & Diane J. Nugent

  3. Institute for Clinical and Translational Science, University of California-Irvine, Irvine, CA, USA

    Thomas J. Kunicki & Diane J. Nugent

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  1. Jeffrey S. Buzby
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Correspondence to Jeffrey S. Buzby.

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Buzby, J.S., Williams, S.A., Imfeld, K.L. et al. Tissue factor inflammatory response regulated by promoter genotype and p38 MAPK in neonatal vs. adult microvascular endothelial cells. Inflamm. Res. 63, 299–308 (2014). https://doi.org/10.1007/s00011-013-0701-5

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  • DOI: https://doi.org/10.1007/s00011-013-0701-5

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