Evaluation of the use of anti-TNF-alpha in an LPS-induced murine model.
OBJECTIVE
Tumor necrosis factor alpha (TNF-alpha) may play a critical role in inflammatory-mediated preterm labor. Medications blocking the activity of TNF-alpha have been shown to be effective in the treatment of conditions such as rheumatoid arthritis; however, the use of these medications for an event like preterm birth or fetal death is unknown. We hypothesized that treatment with anti-TNF-alpha may decrease the rate of fetal death and preterm birth in a LPS-induced murine model.


METHODS
Pregnant C57BL/6J mice received intraperitoneal (IP) injections of either vehicle or 2mg anti-TNF-alpha. After 24h, 10 microg of LPS was administered IP. Mice were sacrificed 24h later and outcomes between groups were assessed. A second set of experiments utilizing RT-PCR was performed to determine the influence of anti-TNF-alpha on production of inflammatory cytokines in response to LPS.


RESULTS
There were 72 resultant pups in the LPS+saline group, and 91 in the group receiving LPS+anti-TNF-alpha. Pretreatment with anti-TNF-alpha reduced the rate of fetal death and preterm birth after LPS administration (p<0.01). Expression of IL-6, IL-1beta, TLR-2, CD14 and COX-1 were found to be significantly reduced in mice treated with anti-TNF-alpha and LPS compared to LPS alone.


CONCLUSIONS
The use of anti-TNF-alpha decreased fetal deaths and preterm deliveries in an LPS-induced model of preterm birth. In addition, there were critical gene expression alterations in the group receiving anti-TNF-alpha. Further evaluation of TNF-alpha blockade as a potential treatment for preterm labor is warranted.
Holmgren
C
C
Department of Obstetrics and Gynecology, University of Utah Health Sciences Center, 20 North 1900 East, Salt Lake City, UT 84132, USA. cholmgren73@yahoo.com
Esplin
M S
MS
Hamblin
S
S
Molenda
M
M
Simonsen
S
S
Silver
R
R
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005313:Fetal Death / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D007752:Obstetric Labor, Premature / Q000517:prevention & control; D011247:Pregnancy; D047928:Premature Birth / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*
D000906:Antibodies; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha