| Abstract: |
TNF is well known for its role in inflammation, including direct effects on the vasculature. TNF also is implicated in the regulation of reproduction by its actions to affect ovarian steroidogenic cells and to induce apoptosis of corpus luteum (CL)-derived endothelial cells in vitro. We hypothesized that the disruption of TNF signaling would postpone the regression of the highly vascularized CL in vivo, and this effect could be replicated in mutant mouse models lacking TNF receptor (TNFRI-/-) and/or a critical enzyme of TNF signaling, acid sphingomyelinase (ASMase-/-). In the current study, the treatment of pseudopregnant mice with the luteolytic mediator prostaglandin F2-α (PGF) significantly increased TNF in the ovaries when compared with saline-treated controls. Treatment with PGF also reduced serum progesterone (P4) concentrations and caused involution of the CL. However, pretreatment of pseudopregnant mice with Etanercept (ETA), a TNF-neutralizing antibody, inhibited the PGF-induced decrease in P4 and delayed luteal regression. A similar outcome was evident in pseudopregnant TNFRI-/- animals. Treatment of luteal microvascular endothelial cells (MVECs) with TNF provoked a significant increase in ASMase activity when compared with the corresponding controls. Furthermore, TNF-induced MVEC death was inhibited in the ASMase-/- mice. The ASMase-/- mice displayed no obvious evidence of luteal regression 24 h after treatment with PGF and were resistant to the PGF-induced decrease in P4. Together these data provide evidence that TNF plays an active role in luteolysis. Further studies are required to determine the deleterious effects of antiinflammatory agents on basic ovarian processes. © 2008 by The National Academy of Sciences of the USA. |
| Keywords: |
signal transduction; controlled study; genetics; nonhuman; comparative study; animal cell; mouse; animal; cytology; metabolism; mouse mutant; animals; mice; mice, knockout; mus; apoptosis; tumor necrosis factor receptor 1; animal experiment; animal model; in vivo study; drug effect; enzyme activity; vascularization; experimental mouse; capillary; physiology; animalia; endothelium cell; endothelial cells; ovary; blood; cytokines; drug antagonism; tumor necrosis factor alpha; tumor necrosis factor-alpha; immunoglobulin g; vascular endothelium; endothelium, vascular; etanercept; down regulation; tumor necrosis factor receptor; involution; sodium chloride; vascular disease; ceramide; ceramides; sphingomyelin phosphodiesterase; receptors, tumor necrosis factor; corpus luteum; progesterone; neutralizing antibody; luteal phase; prostaglandin f2 alpha; tumor necrosis factor antibody; acid sphingomyelinase 1; acid sphingomyelinase-1; tnfr fc fusion protein; tnfr-fc fusion protein; tnfrsf1a protein, mouse; luteolysis; progesterone blood level; pseudopregnancy; steroid metabolism; capillaries; dinoprost; receptors, tumor necrosis factor, type i
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