Preterm delivery is the chief problem in obstetrics today, accounting for 70 percent of perinatal mortality and nearly half of long-term neurologic morbidity.1,2 Approximately 10 percent of all births are preterm, but most of the serious illness and death is concentrated in the 1 to 2 percent of infants who are born at less than 32 weeks of gestation and who weigh less than 1500 g. Approximately 20 percent of preterm births are the result of a physician's decision to bring about delivery for maternal or fetal indications, and the remainder follow the spontaneous onset of labor or rupture . . .

Intrauterine infection and preterm delivery.

The matrix metalloproteinases (MMPs) form an enzyme family of which gelatinase B (MMP-9) represents the largest and most complex member. We focus here on the biochemical properties, regulation, and functions of gelatinase B. The tight regulation of gelatinase B activity is highly complex and is established at five different levels. The transcription of the gelatinase B-gene depends on various cis-elements in its gene promotor and is induced or repressed by a large variety of soluble factors, including cytokines, growth factors, and hormones and by cellular contacts acting through specific signaling pathways. The specific regulation of its secretion occurs in cells storing gelatinase B in granules. After secretion, progelatinase B must be activated through an activation network. The enzyme activity is further regulated by inhibition and by other mechanisms, such as fine-tuning and stabilization by glycosylation. The ability of gelatinase B to degrade components of the extracellular matrix and to regulate the activity of a number of soluble proteins confers an important role in various physiological and pathological processes. These include reproduction, growth, development, inflammation, and vascular and proliferative diseases.

Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)

Cytokines, Prostaglandins and Parturition—A Review

Each of the proinflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF) alpha has been identified in reproductive tissues during labor. The cellular origin of these cytokines is unclear. The aim of this study was to localize these proinflammatory cytokines in myometrium (upper and lower segment), cervix, and fetal membranes at term. Biopsies were taken from women undergoing cesarean section either before or after the onset of labor. Immunohistochemistry was used to localize each of the cytokines IL-1beta, IL-6, IL-8, and TNFalpha. Leukocytes were localized using an antibody to CD45. In myometrium and cervix, immunostaining for IL-1beta was predominantly in leukocytes. In fetal membranes, IL-1beta localized to leukocytes and to the stromal cells of the decidua. In myometrium, IL-6, IL-8, and TNFalpha were restricted to leukocytes, which were present in greater numbers in tissue obtained during labor. In cervix, IL-6, IL-8, and TNFalpha localized to leukocytes and glandular and surface epithelium. IL-8 also localized to cervical stromal cells. In fetal membranes, IL-6 and TNFalpha were expressed by decidual stromal cells, infiltrating leukocytes, and extravillous trophoblasts. In membranes, IL-8 localized to leukocytes in the chorion but was not detected in the amnion. In fetal membranes collected at labor, IL-8 was expressed in decidual stromal cells. Infiltrating leukocytes are a major source of cytokines in uterine tissues during labor.

https://bioone.org/journals/Biology-of-Reproduction/volume-66/issue-2/biolreprod66.2.445/Immunolocalization-of-Proinflammatory-Cytokines-in-Myometrium-Cervix-and-Fetal-Membranes/10.1095/biolreprod66.2.445.pdf

Immunolocalization of Proinflammatory Cytokines in Myometrium, Cervix, and Fetal Membranes During Human Parturition at Term

Labor resembles an inflammatory response that includes secretion of cytokines/chemokines by resident and infiltrating immune cells into reproductive tissues and the maternal/fetal interface. Untimely activation of these inflammatory pathways leads to preterm labor, which can result in preterm birth. Preterm birth is a major determinant of neonatal mortality and morbidity; therefore, the elucidation of the process of labor at a cellular and molecular level is essential for understanding the pathophysiology of preterm labor. Here, we summarize the role of innate and adaptive immune cells in the physiological or pathological activation of labor. We review published literature regarding the role of innate and adaptive immune cells in the cervix, myometrium, fetal membranes, decidua and the fetus in late pregnancy and labor at term and preterm. Accumulating evidence suggests that innate immune cells (neutrophils, macrophages and mast cells) mediate the process of labor by releasing pro-inflammatory factors such as cytokines, chemokines and matrix metalloproteinases. Adaptive immune cells (T-cell subsets and B cells) participate in the maintenance of fetomaternal tolerance during pregnancy, and an alteration in their function or abundance may lead to labor at term or preterm. Also, immune cells that bridge the innate and adaptive immune systems (natural killer T (NKT) cells and dendritic cells (DCs)) seem to participate in the pathophysiology of preterm labor. In conclusion, a balance between innate and adaptive immune cells is required in order to sustain pregnancy; an alteration of this balance will lead to labor at term or preterm.

/pdf/immune-cells-in-term-and-preterm-labor-2g468h0vbp.pdf

Immune cells in term and preterm labor

A relationship was sought between the tissue concentrations of interleukin (IL)-8, matrix metalloproteinase (MMP)-8 and MMP-9, and the numbers of the various leukocytes infiltrating the lower uterine segment stroma during parturition. Biopsy specimens of the lower uterine segment were obtained from 63 women undergoing Caesarean section at various stages of cervical dilatation at term. The concentrations of IL-8, MMP-8 and MMP-9 were determined with enzyme-linked immunosorbent assays, and the leukocytes were quantified immunohistochemically. The median IL-8 concentration (pg/mg total protein) rose significantly from 17.2 at 6 cm dilatation. The median MMP-8 concentration (ng/mg total protein) increased significantly from 32.2 at 6 cm dilatation. The median MMP-9 concentration (ng/mg total protein) rose significantly from 15.4 at 6 cm dilatation. The number of neutrophils was significantly higher at 4-6 cm and > 6 cm dilatation than at > 2 cm, reaching maximum values at > 6 cm dilatation. The findings in this study support the hypothesis that IL-8-induced infiltration of the cervical stroma by neutrophils and subsequent release of proteinases may play a key role in parturition.

/pdf/parturition-at-term-parallel-increases-in-interleukin-8-and-2j7kqjtccq.pdf

Parturition at term: parallel increases in interleukin-8 and proteinase concentrations and neutrophil count in the lower uterine segment

Interleukin-1beta and interleukin-8 concentrations in the lower uterine segment during parturition at term.

Collagenolysis in the lower uterine segment during parturition at term: Correlations with stage of cervical dilatation and duration of labor

Aims: To determine the concentrations of tumor necrosis factor a, interleukin-1β, interleukin-6, and interleukin-8 in the lower uterine segment during preterm parturition. Methods: In 71 patients who delivered prematurely by non-elective cesarean tissue specimens were obtained from the lower uterine segment. The patients were grouped in relation to the stage of cervical dilatation ( 6-12 h; > 12 h), and parity (1 versus > 1). Cytokine concentrations in protein extracts of the tissue samples were measured using enzyme-linked immunosorbent assays. Results: Median concentration of tumor necrosis factor α did not change, but that of interleukin-1β, interleukin-6, and interleukin-8 were significantly higher at 2-<4cm than at < 2 cm cervical dilatation (6.6, 67.7, and 125.8 versus 1.1, 17.6, and 22.2 pg/mg protein, respectively). The concentrations of interleukin-6 and interleukin-8 showed a further increase at ≥ 4 cm (297.2 and 468.6 pg/mg, respectively), but for interleukin-1β a decrease was observed (0.6 pg/mg). Cytokine concentrations were not related to duration of labor or parity. Conclusions: Local inflammation-associated changes that are mainly related to the stage of cervical dilatation and to only a minor degree to uterine activity may play a crucial role in preterm parturition.

Tissue concentrations of cytokines in the lower uterine segment during preterm parturition.

Objective

We have previously shown that human articular chondrocytes synthesize large amounts of interleukin-6 (IL-6) upon stimulation with proinflammatory cytokines and that they express the IL-6 receptor. The present study was undertaken to analyze whether different IL-6–type cytokines can induce synthesis of the acute-phase protein α1-antitrypsin in human articular chondrocytes.



Methods

Chondrocytes from human articular cartilage, cultured in agarose, were stimulated with IL-6–type cytokines. Total RNA was isolated and analyzed by Northern blotting. Levels of α1-antitrypsin protein were determined by enzyme immunoassay.



Results

Stimulation of chondrocytes with oncostatin M (OSM) and IL-6 led to a 5–10-fold increase in α1-antitrypsin synthesis. This increase was dose and time dependent. Furthermore, OSM and IL-6 induced IL-6 synthesis in chondrocytes, resulting in an autocrine amplification loop.



Conclusion

Our data strongly suggest the existence of a local acute-phase response in the joint. Synthesis of the acute-phase protein α1-antitrypsin, a major inhibitor of serine proteinases, may be an important protective mechanism of articular chondrocytes to prevent cartilage damage in inflammatory joint diseases.

Induction of α1-ANTITRYPSIN synthesis in human articular chondrocytes by interleukin-6-type cytokines : Evidence for a local acute-phase response in the joint

Dagmar-Christiane Fischer

Papers

Parturition at term: parallel increases in interleukin-8 and proteinase concentrations and neutrophil count in the lower uterine segment

Interleukin-1beta and interleukin-8 concentrations in the lower uterine segment during parturition at term.

Collagenolysis in the lower uterine segment during parturition at term: Correlations with stage of cervical dilatation and duration of labor

Tissue concentrations of cytokines in the lower uterine segment during preterm parturition.

Induction of α1-ANTITRYPSIN synthesis in human articular chondrocytes by interleukin-6-type cytokines : Evidence for a local acute-phase response in the joint