Characterization of RAGE, HMGB1, and S100beta in inflammation-induced preterm birth and fetal tissue injury.
Immune activation represents an adaptive reaction triggered by both noxious exogenous (microbes) and endogenous [high mobility group box-1 protein (HMGB1), S100 calcium binding proteins] inducers of inflammation. Cell stress or necrosis lead the release of HMGB1 and S100 proteins in the extracellular compartment where they act as damage-associated molecular pattern molecules (or alarmins) by engaging the receptor for advanced glycation end-products (RAGE). Although the biology of RAGE is dictated by the accumulation of damage-associated molecular pattern molecules at sites of tissue injury, the role of RAGE in mediating antenatal fetal injury remains unknown. First, we studied the relationships at birth between the intensity of human fetal inflammation and sRAGE (an endogenous RAGE antagonist), HMGB1, and S100beta protein. We found significantly lower sRAGE in human fetuses that mounted robust inflammatory responses. HMGB1 levels correlated significantly with levels of interleukin-6 and S100beta in fetal circulation. We then evaluated the levels and areas of tissue expression of RAGE, HMGB1, and S100beta in specific organs of mouse fetuses on E16. Using an animal model of endotoxin-induced fetal damage and preterm birth, we determined that inflammation induces a significant change in expression of RAGE and HMGB1, but not S100beta, at sites of tissue damage. Our findings indicate that RAGE and HMGB1 may be important mediators of cellular injury in fetuses delivered in the setting of inflammation-induced preterm birth.
Buhimschi
Catalin S
CS
Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University, 333 Cedar Street, New Haven, CT 06520, USA. catalin.buhimschi@yale.edu
Baumbusch
Margaret A
MA
Dulay
Antonette T
AT
Oliver
Emily A
EA
Lee
Sarah
S
Zhao
Guomao
G
Bhandari
Vineet
V
Ehrenkranz
Richard A
RA
Weiner
Carl P
CP
Madri
Joseph A
JA
Buhimschi
Irina A
IA
D000818:Animals; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D005333:Fetus / Q000276:immunology / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000096:biosynthesis*; D024243:HMGB1 Protein / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000276:immunology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000096:biosynthesis*
D004731:Endotoxins; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D015850:Interleukin-6; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins
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