Myometrial Tumor Necrosis Factor-α Receptors Increase With Gestation and Labor and Modulate Gene Expression Through Mitogen-Activated Kinase and Nuclear Factor-κB
Previously, we found that myometrial tumor necrosis factor-α (TNF-α) messenger RNA (mRNA) expression did not increase with preterm or term labor. To further investigate the role of TNF-α in human labor, we studied TNF-α receptor (TNFR1A and B) expression, regulation, and associated intracellular signaling pathways in human myometrial samples obtained both before and after the onset of labor and in primary cultures of uterine smooth muscle cells (USMCs). We found that the mRNA expression of both receptors increased with advancing gestation and labor and protein levels of TNFR1B were significantly higher in term laboring myometrial samples than in nonlabor controls. Tumor necrosis factor-ᾳ treatment of USMCs activated all mitogen-activated protein kinase (MAPK) subtypes and nuclear factor κ-B (NF-κB). The TNF-α induced increases in the expression of TNFR1B and prostaglandin H synthase type 2 were reduced by inhibitors of NF-κB and MAPKs, respectively. The TNF-α induced increase in interleukin 8 (IL-8) appeared to be independent of MAPK and NF-κB pathway. These data suggest that the uterus may become more sensitive to the action of TNF-α with advancing gestation and labor and that TNF-α acts via MAPK and NF-κB to promote labor-associated gene expression.
Keywordslabor myometrium tumor necrosis factor-α inflammation pro-labor genes
Unable to display preview. Download preview PDF.
- 11.Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labour is induced by intraamniotic infusions of interleukin-1beta and tumour necrosis factor- alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006;195(6):1578–1589.PubMedPubMedCentralCrossRefGoogle Scholar
- 12.Romero R, Mazor M, Wu YK, et al. Infection in the pathogenesis of preterm labor. Seminars Perinatol. 1988;12(4):262–279.Google Scholar
- 29.Tabibzadeh S, Zupi E, Babaknia A, Liu R, Marconi D, Romanini C. Site and menstrual cycle-dependent expression of proteins of the tumour necrosis factor (TNF) receptor family, and BCL-2 oncoprotein and phase-specific production of TNF alpha in human endometrium. Hum Reprod. 1995;10(2):277–286.CrossRefGoogle Scholar
- 32.Reddy J, Chastagner P, Fiette L, Liu X, Thèze J. IL-2 induced tumour necrosis factor (TNF)-beta expression: further analysis in the IL-2 knockout model, and comparison with TNF-alpha, lymphotoxin-beta, TNFR1 and TNFR2 modulation. Int Immunol. 2001;13(2):135–147.PubMedCrossRefPubMedCentralGoogle Scholar
- 39.Lin CC, Hsiao LD, Chien CS, Lee CW, Hsieh JT, Yang CM. Tumour necrosis factor-α-induced cyclooxygenase-2 expression in human tracheal smooth muscle cells: involvement of p42/44 and p38 mitogen-activated protein kinases and nuclear factor-KB. Cell Signal. 2004;16(5):597–607.PubMedCrossRefPubMedCentralGoogle Scholar
- 47.Chen YM, Chiang WC, Lin SL, Wu KD, Tsai TJ, Hsieh BS. Dual regulation of tumor necrosis factor-alpha-induced CCL2/monocyte chemoattractant protein-1 expression in vascular smooth muscle cells by nuclear factor-kappaB and activator protein-1: modulation by type III phosphodiesterase inhibition. J Pharmacol Exp Ther. 2004;309(3):978–986.PubMedCrossRefGoogle Scholar
- 51.Wu WT, Chi KH, Ho FM, Tsao WC, Lin WW. Proteasome inhibitors up-regulate haem oxygenase-1 gene expression: requirement of p38 MAPK (mitogen-activated protein kinase) activation but not of NF-kappaB (nuclear factor kappaB) inhibition. Biochem J. 2004; 379(Pt 3):587–593.PubMedPubMedCentralCrossRefGoogle Scholar