Effect of sodium butyrate on lung vascular TNFSF15 (TL1A) expression: differential expression patterns in pulmonary artery and microvascular endothelial cells.
Vascular endothelial growth inhibitor TNFSF15 (TL1A), a ligand for TNFRSF25 (DR3) and decoy receptor TNFRSF6B (DcR3), is expressed in human pulmonary arterial (HPAEC) and lung microvascular (HMVEC) endothelial cells where it might modulate inflammation and sickle vasculopathy. Pulmonary disease, endothelial abnormalities and inflammation are prominent features of sickle cell disease (SCD). Butyrate has opposing effects on endogenous TNFSF15 expression in pulmonary endothelium, acting as an inhibitor in HPAEC and an inducer in HMVEC. Similar effects were observed with a known cytokine TNF-alpha in these two cell types. Furthermore the TNFSF15 promoter utilized different combinations of cis-elements for its expression in these two cell types. AP1-like and G-rich sequence elements were critical for promoter activity in large vessel HPAEC while AP1-like and NF-kappaB consensus sequence elements were required in small vessel HMVEC. The requirement of an NF-kappaB sequence element by the TNFSF15 promoter in HMVEC but not in HPAEC supported the notion that HMVEC might be a target of inflammation and vasoocclusion in SCD. The dual effects of butyrate-dependant TNFSF15 regulation in lung endothelium may help in identify inflammatory pathways and understand the role of HMVEC in pathogenesis of vasoocclusion in SCD.
Safaya
Surinder
S
Center of Excellence in Sickle Cell Disease and Division of Hematology/Oncology, 88 East Newton St., Boston, MA 02118, USA. ssafaya@bu.edu
Klings
Elizabeth S
ES
Odhiambo
Adam
A
Li
Guihua
G
Farber
Harrison W
HW
Steinberg
Martin H
MH
D002460:Cell Line; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008833:Microcirculation; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000187:drug effects*; D012978:Sodium Oxybate / Q000494:pharmacology*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D008024:Ligands; D016328:NF-kappa B; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D012978:Sodium Oxybate