Pregnancy-linked suppression of TcR signaling pathways by a circulating factor absent in recurrent spontaneous pregnancy loss (RPL).
Evidence suggests that maternal cell-mediated immunity is suppressed during pregnancy and that failure to suppress immune responses can result in partial or total rejection of the fetus. The molecular events associated with suppression of maternal T-cell activation mediated by circulating pregnancy-associated 14 kDa zeta inhibitor protein (ZIP) were defined in women with and without histories of recurrent pregnancy loss (RPL). Using cDNA microarray analysis, ZIP modulations of specific genes associated with T-cell activation signaling were defined. Alterations of defined components were confirmed at the protein level using chromatographically purified ZIP from normal pregnancies versus analogous material from women experiencing RPL. Based on microarray analyses, ZIP from normal pregnancies induced an increase (> or =2-fold) in the expression of 19 genes and a decrease (> or =2-fold) in 15 genes, when incubated with cultured T-cells. In contrast, when T-cells were incubated with analogous material from RPL or non-pregnant controls, no significant differences were observed in the expression of these genes. At the protein level, ZIP from normal pregnancies induced decreases in CD3-zeta (2.36-fold), JAK3 (2.41-fold), STAT5 (1.85-fold), and NF-kappaB (4.24-fold) and a 2.05-fold increase in SOCS2 (all at p<0.001 compared to RPL and non-pregnant controls). The suppressive effects of Zip can lead to the failure of T-cell production of Th1 cytokines, such as IL-2. The 14 kDa circulating ZIP from normal pregnancies suppressed components within the JAK/STAT pathway and induced suppressors of cytokine stimulation, SOCS2.
Taylor
Douglas D
DD
Department of Obstetrics, Gynecology, and Women's Health, Division of Gynecologic Oncology, University of Louisville School of Medicine, 511 South Floyd Street, MDR 420, Louisville, KY 40292, USA. ddtaylor@louisville.edu
Bohler
Henry C
HC
Gercel-Taylor
Cicek
C
D000026:Abortion, Habitual / Q000276:immunology* / Q000378:metabolism*; D000328:Adult; D017252:CD3 Complex / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D007376:Interleukin-2; D016328:NF-kappa B; D011257:Pregnancy Proteins; D011948:Receptors, Antigen, T-Cell; C510332:zeta inhibitor protein 14 kDa, human