Increased synthesis of tumor necrosis factor-alpha in uterine explants from pregnant diabetic rats and in primary cultures of uterine cells in high glucose.
The production of tumor necrosis factor-alpha (TNF-alpha) was investigated in uterine explants from normal, diabetic, or insulin-treated diabetic pregnant rats. Explants from diabetic rats released more soluble TNF-alpha than did those in the other groups. The extent of this secretion was correlated with blood glucose concentration at the time of explantation. The concentration of cell membrane-associated TNF-alpha in the explants was not altered by diabetes. Daily insulin administration failed to normalize uterine TNF-alpha secretion despite correction of glycemia in the diabetic rats. Explants from normal pregnant rats cultured in vitro with increasing concentrations of D-glucose showed a dose-dependent increase in TNF-alpha secretion. The production of TNF-alpha in high glucose was also tested in primary cultures of uterine cells isolated from either immature or adult rats. TNF-alpha secretion was increased in high D-glucose but not in iso-osmolar concentrations of L-glucose, D-raffinose, D-galactose, or mannitol. Cell membrane-associated TNF-alpha was not influenced by high D-glucose. Semiquantitative reverse transcription-amplification of RNA extracted from primary cultures of uterine cells showed that the steady-state level of TNF-alpha transcripts was increased by high D-glucose but not by high L-glucose. The results are consistent with the hypothesis that hyperglycemia is instrumental in the overexpression of TNF-alpha in the diabetic uterus. Because TNF-alpha has a demonstrated negative impact on embryonic growth, enhanced TNF-alpha synthesis in the pregnant uterus may contribute to the embryopathy associated with maternal diabetes.
Pampfer
S
S
Physiology of Reproduction Research Unit, University of Louvain Medical School, Brussels, Belgium. pampfer@obst.ucl.ac.be
Vanderheyden
I
I
De Hertogh
R
R
D000818:Animals; D002241:Carbohydrates / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000737:chemistry / Q000494:pharmacology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D002241:Carbohydrates; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose