Neutrophils as sources of dinucleotide polyphosphates and metabolism by epithelial ENPP1 to influence barrier function via adenosine signaling
MOLECULAR BIOLOGY OF THE CELL
Authors: Curtis, Valerie F.; Cartwright, Ian M.; Lee, J. Scott; Wang, Ruth X.; Kao, Daniel J.; Lanis, Jordi M.; Burney, Krista M.; Welch, Nichole; Hall, Caroline H. T.; Goldberg, Matthew S.; Campbell, Eric L.; Colgan, Sean P.
Abstract
Extracellular adenosine signaling is established as a protective component in mucosal inflammatory responses. The sources of extracellular adenosine include enzymatic processing from nucleotides, such as ATP and AMP, that can be liberated from a variety of cell types, including infiltrating leukocytes. Here we demonstrate that activated human neutrophils are a source of diadenosine triphosphate (Ap3A), providing an additional source of nucleotides during inflammation. Profiling murine enteroids and intestinal epithelial cell lines revealed that intestinal epithelia prominently express apical and lateral ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1), a member of the ENPP family of enzymes that metabolize diadenosine phosphates, especially Ap3A. Extensions of these studies demonstrated that intestinal epithelia metabolize Ap3A to ADP and AMP, which are further metabolized to adenosine and made available to activate surface adenosine receptors. Using loss and gain of ENPP1 approaches, we revealed that ENPP1 coordinates epithelial barrier formation and promotes epithelial wound healing responses. These studies demonstrate the cooperative metabolism between Ap3A and ENPP1 function to provide a significant source of adenosine, subserving its role in inflammatory resolution.
Candidate gene linkage approach to identify DNA variants that predispose to preterm birth
PEDIATRIC RESEARCH
Authors: Bream, Elise N. A.; Leppellere, Cara R.; Cooper, Margaret E.; Dagle, John M.; Merrill, David C.; Christensen, Kaare; Simhans, Hyagriv N.; Fong, Chin-To; Hallman, Mikko; Muglia, Louis J.; Marazita, Mary L.; Murray, Jeffrey C.
Abstract
BACKGROUND: The aim of this study was to identify genetic variants contributing to preterm birth (PTB) using a linkage candidate gene approach. METHODS: We studied 99 single-nucleotide polymorphisms (SNPs) for 33 genes in 257 families with PTBs segregating. Nonparametric and parametric analyses were used. Premature infants and mothers of premature infants were defined as affected cases in independent analyses. RESULTS: Analyses with the infant as the case identified two genes with evidence of linkage: CRHR1 (P = 0.0012) and CYP2E1 (P = 0.0011). Analyses with the mother as the case identified four genes with evidence of linkage: ENPP1 (P = 0.003), IGFBP3 (P = 0.006), DHCR7 (P = 0.009), and TRAF2 (P = 0.01). DNA sequence analysis of the coding exons and splice sites for CRHR1 and TRAF2 identified no new likely etiologic variants. CONCLUSION: These findings suggest the involvement of six genes acting through the infant and/or the mother in the etiology of PTB.
COA
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