Use of cDNA arrays to generate differential expression profiles for inflammatory genes in human gestational membranes delivered at term and preterm.

Inflammatory processes are implicated in preterm labour (PTL). To identify potential novel markers for PTL, we have used commercial cDNA arrays to generate profiles of differential expression of inflammation-associated genes in gestational membranes with term and PTL. RNA for cDNA probe synthesis was isolated from reflected human amnion and choriodecidua membranes delivered following Caesarean section at term before the onset of labour (TNL, n = 4), spontaneous labour at term (TSL, n = 4), and PTL with and without chorioamnionitis (PTL(+INF) and PTL(-INF) respectively, n = 4 each). Profiles were displayed relative to TNL and statistical comparisons of TSL versus TNL and PTL(+INF) versus PTL(-INF) were performed. Elevated expression of chemokines macrophage inflammatory protein 1beta(MIP-1beta) and pulmonary and activation-regulated chemokine (PARC) was observed in PTL(+INF) compared to PTL(-INF) amnion and choriodecidua respectively (P = 0.03). Likewise, the cytokines oncostatin-M and pre-B cell enhancing factor (PBEF) were more highly expressed in PTL(+INF) compared with PTL(-INF) and in TSL compared with TNL respectively (P = 0.03). Conversely, inhibin A, tissue inhibitors of matrix metalloproteinase (TIMP)-3 and TIMP-4 were all significantly elevated in PTL(-INF) compared with PTL(+INF) (P = 0.03). Furthermore, differential expression patterns of classes of genes, grouped according to function (e.g. chemokines), were noted. The cDNA array approach holds promise for identification of new candidate markers or combinations thereof for prediction or diagnosis of PTL, as well as for increasing our understanding of the particular aetiologies involved.

[1]  G. Rizzo,et al.  Ultrasonographic assessment of the uterine cervix and interleukin‐8 concentrations in cervical secretions predict intrauterine infection in patients with preterm labor and intact membranes , 1998, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[2]  M Galasso,et al.  Macrophage Inflammatory Protein‐1α in Term and Preterm Parturtition: Effect of Microbial Invasion of the Amniotic Cavity , 1994, American journal of reproductive immunology.

[3]  D. Dudley.  Pre-term labor: an intra-uterine inflammatory response syndrome? , 1997, Journal of reproductive immunology.

[4]  R. Romero,et al.  The natural interleukin-1 receptor antagonist in the fetal, maternal, and amniotic fluid compartments: the effect of gestational age, fetal gender, and intrauterine infection. , 1994, American journal of obstetrics and gynecology.

[5]  M. Hallman,et al.  Cytokines released by granulocytes and mononuclear cells stimulate amnion cell prostaglandin E2 production. , 1994, Prostaglandins.

[6]  R. Romero,et al.  Neutrophil attractant/activating peptide-1/interleukin-8: association with histologic chorioamnionitis, preterm delivery, and bioactive amniotic fluid leukoattractants. , 1993, American journal of obstetrics and gynecology.

[7]  A. Malmström,et al.  Interleukin-8 is a mediator of the final cervical ripening in humans. , 1997, European journal of obstetrics, gynecology, and reproductive biology.

[8]  L. Teot,et al.  Amniotic fluid interleukin-6 levels correlate with histologic chorioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. , 1993, American journal of obstetrics and gynecology.

[9]  R W Kelly,et al.  Interleukin-8 production by the human cervix. , 1993, American journal of obstetrics and gynecology.

[10]  B. Mercer,et al.  PRETERM LABOR AND PRETERM PREMATURE RUPTURE OF THE MEMBRANES Diagnosis and Management , 1997 .

[11]  E. Nemeth,et al.  Fetal membrane distention: II. Differentially expressed genes regulated by acute distention in vitro. , 2000, American journal of obstetrics and gynecology.

[12]  G. Rizzo,et al.  Interleukin-6 Concentrations in Cervical Secretions in the Prediction of Intrauterine Infection in Preterm Premature Rupture of the Membranes , 1998, Gynecologic and Obstetric Investigation.

[13]  K. Shimoya,et al.  Value of the maternal interleukin 6 level for determination of histologic chorioamnionitis in preterm delivery. , 1997, Gynecologic and obstetric investigation.

[14]  M D Mitchell,et al.  Interleukin (IL)-6 and IL-8 production by human amnion: regulation by cytokines, growth factors, glucocorticoids, phorbol esters, and bacterial lipopolysaccharide. , 1997, Biology of reproduction.

[15]  P. Ruck,et al.  Collagenolysis in the lower uterine segment during parturition at term: correlations with stage of cervical dilatation and duration of labor. , 1999, American journal of obstetrics and gynecology.

[16]  J. Copel,et al.  The role of amniotic fluid L-selectin, GRO-alpha, and interleukin-8 in the pathogenesis of intraamniotic infection. , 1998, American journal of obstetrics and gynecology.

[17]  J. Halgunset,et al.  Cytokine levels in amniotic fluid and inflammatory changes in the placenta from normal deliveries at term. , 1994, European journal of obstetrics, gynecology, and reproductive biology.

[18]  R. Young,et al.  Biomedical Discovery with DNA Arrays , 2000, Cell.

[19]  M. Mitchell,et al.  Intercellular Adhesion Molecule‐1 (ICAM‐1) in Cervicovaginal Fluid of Women Presenting with Preterm Labor: Predictive Value for Preterm Delivery , 2000, American journal of reproductive immunology.

[20]  S. Ognjanovic,et al.  Genomic organization of the gene coding for human pre-B-cell colony enhancing factor and expression in human fetal membranes. , 2001, Journal of molecular endocrinology.

[21]  R. Goldenberg,et al.  A multicenter study of preterm birth weight and gestational age-specific neonatal mortality. , 1993, American journal of obstetrics and gynecology.

[22]  M. Mitchell,et al.  Clinical value of amniotic fluid interleukin‐6 determinations in the management of preterm labour , 1994, British journal of obstetrics and gynaecology.

[23]  C. Pauerstein,et al.  Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety. , 1993, American journal of obstetrics and gynecology.

[24]  H. Watari,et al.  Pro-inflammatory cytokines induce expression of matrix-metabolizing enzymes in human cervical smooth muscle cells. , 1999, The American journal of pathology.

[25]  C. Lockwood,et al.  Markers of risk for preterm delivery , 1999, Journal of perinatal medicine.

[26]  J. K. Pollard,et al.  Intrauterine infection and the effects of inflammatory mediators on prostaglandin production by myometrial cells from pregnant women. , 1996, American journal of obstetrics and gynecology.

[27]  D. Arduini,et al.  Interleukin-6 concentrations in cervical secretions identify microbial invasion of the amniotic cavity in patients with preterm labor and intact membranes. , 1996, American journal of obstetrics and gynecology.

[28]  J. Woessner,et al.  Collagenase, its inhibitors, and decorin in the lower uterine segment in pregnant women. , 1993, American journal of obstetrics and gynecology.

[29]  N. Papadogiannakis.  Traffic of leukocytes through the maternofetal placental interface and its possible consequences. , 1997, Current topics in microbiology and immunology.

[30]  H. Kodama,et al.  The role of cytokines in cervical ripening: correlations between the concentrations of cytokines and hyaluronic acid in cervical mucus and the induction of hyaluronic acid production by inflammatory cytokines by human cervical fibroblasts. , 1998, American journal of obstetrics and gynecology.

[31]  L. Keski-Nisula,et al.  Intrauterine inflammation at term: a histopathologic study. , 2000, Human pathology.

[32]  R. Menon,et al.  MMP/TIMP imbalance in amniotic fluid during PROM: an indirect support for endogenous pathway to membrane rupture , 1999, Journal of perinatal medicine.

[33]  H. Nagase,et al.  Tumor necrosis factor α (TNFα) induces pro‐matrix metalloproteinase 9 production in human uterine cervical fibroblasts but interleukin 1 α antagonizes the inductive effect of TNFα , 1996 .

[34]  J. Morrison,et al.  Preterm birth: A puzzle worth solving , 1990, Obstetrics and gynecology.

[35]  M. Mitchell,et al.  Inflammatory Cytokine mRNA in Human Gestational Tissues: Implications for Term and Preterm Labor , 1996, The Journal of the Society for Gynecologic Investigation: JSGI.

[36]  L. Tashima,et al.  Fetal membrane distention: I. Differentially expressed genes regulated by acute distention in amniotic epithelial (WISH) cells. , 2000, American journal of obstetrics and gynecology.

[37]  N. Takai,et al.  Interleukin-1beta and interleukin-8 in cervicovaginal fluid during pregnancy. , 1998, American journal of obstetrics and gynecology.

[38]  M. Mitchell,et al.  Cytokine abundance in placental tissues: evidence of inflammatory activation in gestational membranes with term and preterm parturition. , 1999, American journal of obstetrics and gynecology.

[39]  N. Kiviat,et al.  The Relationship of Amniotic Fluid Cytokines and Preterm Delivery, Amniotic Fluid Infection, Histologic Chorioamnionitis, and Chorioamnion Infection , 1993, Obstetrics and gynecology.

[40]  W. Rath,et al.  Biochemical events in cervical ripening dilatation during pregnancy and parturition. , 1995, Journal of obstetrics and gynaecology.

[41]  W. Hill,et al.  Risks and complications of tocolysis. , 1995, Clinical obstetrics and gynecology.

[42]  W. Rath,et al.  [The role of cytokines in the induction of labor, cervical ripening and rupture of the fetal membranes]. , 1996, Zeitschrift fur Geburtshilfe und Neonatologie.

[43]  I McNiece,et al.  Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor , 1994, Molecular and cellular biology.

[44]  S. Palmer,et al.  Effect of Relaxin on Tissue Inhibitor of Metalloproteinase‐1 and ‐2 in the Porcine Uterus and Cervix , 1999, Annals of the New York Academy of Sciences.

[45]  L. Vatten,et al.  TNF, IL-1, IL-6, IL-8 and soluble TNF receptors in relation to chorioamnionitis and premature labor , 1998, Journal of perinatal medicine.

[46]  F. Denison,et al.  Secretory leukocyte protease inhibitor concentration increases in amniotic fluid with the onset of labour in women: characterization of sites of release within the uterus. , 1999, The Journal of endocrinology.

[47]  Roberto Romero,et al.  GROα in the Fetomaternal and Amniotic Fluid Compartments During Pregnancy and Parturition , 1996 .

[48]  R. Goldenberg,et al.  Current concepts on the pathogenesis and markers of preterm births. , 2000, Clinics in perinatology.

[49]  H. Kitagawa,et al.  Prostaglandin E2 production by endogenous secretion of interleukin-1 in decidual cells obtained before and after the labor. , 1996, Prostaglandins.

[50]  M. Mitchell,et al.  Macrophage Inflammatory Protein-1α Regulates Prostaglandin E2 and Interleukin-6 Production by Human Gestational Tissues In Vitro , 1996, The Journal of the Society for Gynecologic Investigation: JSGI.

[51]  J. Neilson,et al.  Interleukin-6, interferon-gamma, interleukin-8, and granulocyte-macrophage colony stimulating factor levels in human amniotic fluid at term. , 1996, Journal of reproductive immunology.

[52]  M. Mitchell,et al.  Enhanced expression of intercellular adhesion molecule-1 (ICAM-1) in amnion with term and preterm labour. , 2000, Placenta.

[53]  P. Hart,et al.  Interleukin 4 production by human amnion epithelial cells and regulation of its activity by glycosaminoglycan binding. , 1995, Biology of reproduction.

[54]  I. Furuta,et al.  Cytokines Concentrations in the Cervical Mucus of Pregnant Women , 1996, The journal of obstetrics and gynaecology research.

[55]  G. Rizzo,et al.  The diagnostic value of interleukin-8 and fetal fibronectin concentrations in cervical secretions in patients with preterm labor and intact membranes , 1997, Journal of perinatal medicine.

[56]  M. Keirse.  New perspectives for the effective treatment of preterm labor. , 1995, American journal of obstetrics and gynecology.

[57]  C L Elliott,et al.  IL‐1β and IL‐8 in Human Fetal Membranes: Changes with Gestational Age, Labor, and Culture Conditions , 2001, American journal of reproductive immunology.

[58]  I. Cameron,et al.  Leukocytes infiltrate the myometrium during human parturition: further evidence that labour is an inflammatory process. , 1999, Human reproduction.

[59]  R. Romero,et al.  Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. , 1997, Infectious disease clinics of North America.

[60]  H. Joller-jemelka,et al.  Cytokine production and visualized effects in the feto-maternal unit. Quantitative and topographic data on cytokines during intrauterine disease. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[61]  T. Terao,et al.  Mechanical stretching induces interleukin-8 gene expression in fetal membranes: a possible role for the initiation of human parturition. , 1996, European journal of obstetrics, gynecology, and reproductive biology.

[62]  J. Copel,et al.  Elevated amniotic fluid levels of leukemia inhibitory factor, interleukin 6, and interleukin 8 in intra-amniotic infection. , 1998, American journal of obstetrics and gynecology.

[63]  R. Romero,et al.  The Value of Amniotic Fluid Interleukin‐6, White Blood Cell Count, and Gram Stain in the Diagnosis of Microbial Invasion of the Amniotic Cavity in Patients at Term , 1994, American journal of reproductive immunology.

[64]  K. Nasu,et al.  Platelet-Activating Factor Induces an Imbalance Between MatrixMetalloproteinase-1 and Tissue Inhibitor of Metalloproteinases-1 Expressionin Human Uterine Cervical Fibroblasts , 2000, Biology of reproduction.

[65]  M D Mitchell,et al.  Interleukin-1 stimulates prostaglandin biosynthesis by human amnion. , 1989, Prostaglandins.

[66]  M. Mitchell,et al.  Regulation of Cultured Human Chorion Cell Chemokine Production by Group B Streptococci and Purified Bacterial Products , 1996, American journal of reproductive immunology.

[67]  D. Taylor,et al.  Increased concentration of pro-matrix metalloproteinase 9 in term fetal membranes overlying the cervix before labor: implications for membrane remodeling and rupture. , 2000, American journal of obstetrics and gynecology.

[68]  J. Ernest,et al.  Fetal fibronectin, interleukin-6, and C-reactive protein are useful in establishing prognostic subcategories of idiopathic preterm labor. , 1995, American journal of obstetrics and gynecology.

[69]  R. Romero,et al.  Interleukin 16 in pregnancy, parturition, rupture of fetal membranes, and microbial invasion of the amniotic cavity. , 2000, American journal of obstetrics and gynecology.

[70]  F. Denison,et al.  Cytokine secretion by human fetal membranes, decidua and placenta at term. , 1998, Human reproduction.

[71]  M. Mitchell,et al.  The molecular mechanisms of term and preterm labor: recent progress and clinical implications. , 1997, Clinical obstetrics and gynecology.

[72]  M. Alexandersson,et al.  Leukocyte subpopulations in the human uterine cervical stroma at early and term pregnancy. , 1997, Human reproduction.

[73]  L. Silberman,et al.  The prevalence and distribution of acute placental inflammation in uncomplicated term pregnancies , 1989, Obstetrics and gynecology.

[74]  I. Hoskins,et al.  Amniotic Fluid Granulocyte Colony Stimulating Factor Levels: A Rapid Marker for Diagnosing Chorioamnionitis , 1997, American journal of reproductive immunology.

[75]  R. Romero,et al.  Amniotic Fluid Interleukin‐6 Determinations Are of Diagnostic and Prognostic Value in Preterm Labor , 1993, American journal of reproductive immunology.

[76]  S. Witkin,et al.  Detection of tumor necrosis factor-α, interleukin-6, and fetal fibronectin in the lower genital tract during pregnancy: Relation to outcome , 1994 .

[77]  M. Mitchell,et al.  Interleukin‐1 Receptor Antagonist (IL‐1ra) Production by Human Amnion, Chorion, and Decidua , 1994, American journal of reproductive immunology.

[78]  S. Brennecke,et al.  Interleukin-8 release from human gestational tissue explants: effects of gestation, labor, and chorioamnionitis. , 1999, Biology of reproduction.