The contribution of the immune system to parturition

The immune system plays a central role before and during parturition, including the main physiological processes of parturition: uterine contractions and cervical ripening. The immune system comprises white blood cells and their secretions. Polymorphonuclear cells and macrophages invade the cervical tissue and release compounds, such as oxygen radicals and enzymes, which break down the cervical matrix to allow softening and dilatation. During this inflammatory process, white blood cells undergo chemotaxis, adherence to endothelial cells, diapedesis, migration and activation. Factors that regulate white blood cell invasion and secretion include cytokines such as tumour necrosis factor and interleukins. Glucocorticoids, sex hormones and prostaglandins, affect cytokine synthesis. They also modulate the target cells, resulting in altered responses to cytokines. On the other hand, the immune system has profound effects on the hormonal system and prostaglandin synthesis. In animals, nitric oxide has marked effects on uterine quiescence during gestation. At the same time, it plays an important role in regulating the vascular tone of uterine arteries and has anti-adhesive effects on leukocytes. Cytokines are found in amniotic fluid, and in maternal and foetal serum at term and preterm. Several intrauterine cells have been shown to produce these cytoldnes. Since neither white blood cells, cytokines nor nitric oxide seem to be the ultimate intermediate for human parturition, the immune system is an additional but obligatory and underestimated component in the physiology of delivery. Scientists, obstetricians and anaesthesiologists must thus be aware of these processes.


Introduction
The effect of anaesthesia, stress and pathological disorders on the process of labour and the mode of delivery remains controversial. Because randomization and clinical research in this field is limited by ethical considerations, the physiology of parturition, especially the underlying autocrine, paracrine and endocrine control must be understood. Therefore, physicians should be familiar with the physiological processes which contribute to myometrial contractions and cervical ripening, and must be aware of recent trends and research.
Until labour, cervical dilatation and particularly labour are suppressed. During parturition, forceful myometrial contractions propel the foetus through the dilated and ripened cervix and vaginal tract. Several cascade pathways including the hormonal system, prostaglandins and the immune system, contribute to elicit or augment cervical ripening and labour.
Hormones such as progesterone, oestrogens and oxytocin may inhibit or induce physiological processes in the uterus, but they fail to explain the entire mechanism of parturition. The discovery of prostaglandins and their contribution to labour was an obstetric revolution with dramatic clinical impact. Prostaglandins are obligatory in parturition, but they are not considered the sole intermediate modulator of this process.
Cervical ripening is an inflammatory process, 2 since polymorphonuclear cells (PMNs) and macrophages are found in abundance in cervical tissue. Cytokines, which are small intercellular signal peptides of the immune system, are found R De Jongh et al.
in varying concentrations in amniotic fluid, foetal several molecules, including (oxygen) radicals; and maternal serum before and during parturi-proteolytic enzymes such as lysozyme, coition. -8 They are capable of modulating prosta-lagenase and elastase; and cytokines such as glandin production. [9][10][11][12] Several foetal and tumour necrosis factor (TNF) and interleukin-1 maternal cells produce these cytokines.  The (IL-1). Macrophages can release chemotactic fact that inflammation contributes to delivery is factors for other inflammatory cells. The most suggested by the finding of irreversible labour important factor is interleukin-8 (IL-8), but leukoand cervical ripening with an increased protrienes and platelet activating factor (PAF) also duction of cytokines during intra-uterine infec-have chemotactic properties. 21 On the other tion. 9-11'17 Moreover, intrauterine but not hand, macrophages can release factors that intraperitoneal bacterial inoculum resulted in inhibit PMN chemotaxis, 22 '23 resulting in the preterm delivery within 2 days. 18 accumulation of PMNs around macrophages. The aim of this article is to propose some During inflammation, the localization of macimmunological processes which might play a role rophages in the tissues allows these cells to comduring cervical ripening and labour. Initially we municate with other adjacent inflammatory cells, describe the function of the inflammatory cells, endothelial cells and fibroblasts. Of particular restricted to monocytes and polymorphonuclear interest is the 'decidua-macrophage connection', cells (PMNs), and their secretion products because the decidua is enriched with boneincluding oxygen radicals, proteases and cyto-marrow-derived macrophages. 24'25 Moreover, kines. Since the inflammatory cells have to decidual cells have macrophage-like functional migrate into tissues, a part of this article sum-characteristics, e.g. the production of PAF and marizes the leucocyte-endothelial cell interaction, several cytokines after endotoxin stimulation. 2 Then the physiological result of inflammation of the cervix and the myometrium is described. In Polymorphonuclear cells: PMNs possess three the last part of this article a summary is given of major types of granules containing over 20 differthe complex interaction of inflammatory and ent enzymes. After stimulation, e.g. by cytokines neurohumoral pathways. Since research on paror complement factors, PMNs degranulate with a turients in this domain is sparse, most of the release of proteases and formation of oxygen information dealing with PMNs, macrophages, radicals, resulting in tissue destruction. The cytokines and oxygen radicals originates from in extent of degranulation or respiratory burst b2 vitro studies or from polytraumatized or septic different stimulators has not been clarified fully. patients or animals. Furthermore, the article has Moreover, after stimulation, PMNs can synthesize not the intention to be complete, but describes many cytokines. basic physiological pathways leading to an under-Because of the presence of large amounts of standing of more specialized articles.
PMNs and macrophages in the near-term cervix, 2'28 and their capacity to produce pro-Th immun system teases, cytokines and oxygen radicals, these cells must form a requisite step in the inflammatory The immune system is classically divided into process of ripening the cervix. an innate branch and an acquired branch. The latter is mainly composed of lymphocytes and Proteases.. Proteases are discussed under the immunoglobulins, and the former mainly of heading'cervical ripening'. monocytes, macrophages, PMNs and natural killer cells (NK). The protein components of the Oxygen radicals: Oxygen radical formation innate branch include complement factors and occurs during normal cell function, but in acute phase proteins (APP). 19 The cells of the normal conditions they are neutralized or innate branch act by producing cytokines, pro-cleared. Sources of oxygen radicals which can teases and oxygen radicals, result in tissue damage, with respect to parturi-Monocytes and macrophages: Monocytes and macrophages roe part of the mononuclear phagocyte system. The macrophage can interact with its environment through the binding of tion, include: Various metabolic steps of eicosanoid metabolism. Toxic oxygen radicals can, by themselves, stimulate eicosanoid metabolic pathways. 29' molecules to specific functional membrane NADPH dehydrogenase and ubiquinonesurface receptors, e.g. for cytokines or comple-cytochrome b complex of the mitochondrial ment fragments. The potent antimicrobial, tumor-electron transport chain. This process is upreicidal and tissue destructing activity of stimulated gulated in pathological conditions. macrophages is explained by the local release of Ischaemia and particularly reperfusion, con-comitant with the conversion of the xanthine kines and their possible role during parturition substrates to uric acid. 32 Short-lasting but are discussed here. recurrent uterine ischaemia, followed by reperfusion, occurs during every myometrial con-Interleukin-I. Interleukin-14 exists in two forms, traction.
IL-lz and IL-113, with only 26% homology. Almost Activation of the PMN (and macrophage) all nucleated cells, but particularly macrophages plasma membrane NADPH oxido-reductase and monocytes, are capable of producing IL-1. enzyme complex, in response to endotoxins Stimuli for IL-1 production are: other cytokines and cytokines. 3'4 such as IL-1 itself, TNF and interferons; endotoxins; antigen-antibody complexes; and the Fc Oxygen is converted to its toxic metabolites: regions of IgG and C5a. Inhibitors of IL-1 proviz. superoxide anion (O2-), hydrogen peroxide duction include steroids, prostaglandin E2 (H202) and hypochlorous acid. The major (PGE2) and ot-melanocyte stimulating hormone. targets of oxygen radicals, with subsequent An engodenously produced IL-1 receptor antagodestruction, include: lipids 5 (cellysis, cytotoxic nist inhibits the effects of IL-1. and mutagenic metabolites), nucleic acids 36 In vitro, the effects of IL-1 in the cytokine (mutagenesis and carcinogenesis) and particu-network are the amelioration of the synthesis of larly proteins 7 (destruction, enzymatic dysfunc-TNF, IL-1, IL-2, IL-6, PAF, prostacyclin, PGE2 and tion). Moreover, adhesion molecules on colony stimulating factor. IL-1 promotes the leukocytes are upregulated by some oxygen adhesiveness of neutrophils, monocytes and radicals. Several antioxidants are known; other white blood cells to the endothelial cell by however, to date none of these agents have been upregulating adhesion molecules on leukocytes, used extensively in clinical practice. Probably the and their ligands on endothelial cells. higher frequency of cervix carcinoma present in In vivo IL-1 is pyrogenic and it plays a key role multiparous compared to nulliparous women is in the interaction of the immune and neuroendoexplained by the oxygen radicals formation crine systems, with increases of ACTH and cortiduring cervical ripening, costerone production. It causes mobilization of PMNs from the bone marrow, resulting in a Cytokines: Cytokines are low molecular weight neutrophilia. Hyaluronic acid and other glycosaproteins, secreted in very small amounts by a minoglycans can stimulate IL-1 production, which variety of cell types. They modify the behaviour in its turn can increase the collagenase and of other cells and are active in very low con-decrease the metalloproteinase inhibitor levels. 4 centrations. One cytokine may have different Considering the stimulatory effects of IL-1 on effects, depending on the type of target cell, the leukocytes, cytokine, and prostaglandin producconcentration and the interaction with other tion, IL-1 forms a major step in the gestational cytokines. All cytokines have their specific mem-inflammatory network. This was underscored by brane receptor(s), which can be shed and somea study in which almost 100% of preterm mice times measured in the plasma. Until now it can aborted after systemic 42 or intra-amniotic 43 IL-1 only be assumed that cytokine receptors (and administration. Interleukin-1 receptor antagonist thus the cytokine effect) found intrauterine prevented this IL-1 induced preterm parturition. 44 during delivery are changed in number, whether 45 by cellular upregulation whether by binding of Interleukin-6. Interleukin-6 can be produced the receptor from the shedded plasma pool. by almost all nucleated cells. For macrophages, In vitro TNF, IL-6 and IL-8 are produced by the most potent stimulator of IL-6 production is several intrauterine cells after stimulation with endotoxin, and for fibroblasts, IL-1 and TNF. endotoxin or other cytokines. Intrauterine Steroids and oestrogens are strong inhibitors of sources of cytokines include decidua, 14'26'8 IL-6 production in both types of cells. The recepinflammatory cells, placental villi, 9 chorion 15 and tor of IL-6 is upregulated or downregulated by endothelial cells. Normal spontaneous labour at steroids, IL-1 and IL-6, depending on the type of term is associated with a moderate rise in the cell studied. amount of TNF, IL-1, and especially IL-6 in IL-6, a pleiotropic cytokine, stimulates prosamniotic fluid. [3][4][5][6] This rise is more pronounced taglandin synthesis and it elicits, with the particiduring intrauterine infection, where a correlation pation of steroids, the production of acute phase was found between IL-6 and the cytokines TNF proteins by hepatocytes. These liver proteins and IL-1. 8 This underscores the dependency of have antiprotease, opsonizing and oxygen radical these cytokines or the same initiating pathways, scavenging properties. It was therefore assumed In contrast to IL-6, neither TNF nor IL-1 is found that IL-6, in initiating this acute phase response, in serum during labour. Some important cyto-was responsible for limiting the inflammatory I De Jongh et al.
reaction to the injured area, viz. the cervix and early delivery than other microbiological tests the myometrium during parturition.
(bacterial culture). 6 Since steroid hormones such IL-6 was found in maternal and foetal serum as progesterone and corticosteroids are capable and the levels correlated strongly with the duraof influencing IL-8 production, and prostation of labour, thus probably also with the extent glandins downregulate the threshold of PMN of cervical ripening and tissue destruction. 7 Since activation after IL-8 stimulation, 52 IL-8 might form the induction of IL-6 synthesis via mRNA takes the final common step of prostaglandin and several hours, the serum IL-6 peak found imme-steroid hormone action in parturition. 13 '14 diately after vaginal delivery implies that inflam-Patients with chorioamnionitis have increased mation during vaginal delivery is mammal before amniotic fluid levels of IL-1, IL-6, IL-8 and TNF.
birth. Interestingly, considering that IL-6 induces Moreover, this condition is known to be resistant fever, it was shown that patients with epidural to current available tocolytic therapy, indicating a analgesia have higher body temperatures after dramatic abortive role of these cytokines. vaginal delivery than those without epidural analgesia. 46 However, in these studies the dura-Leucocyte-endothelial cell interaction: Margination of labour was not included in the statistics tion of leukocytes is attributed to red blood cells as a dependent variable, although it is known which gather behind leukocytes in capillaries and that patients with prolonged labour are more push them toward the capillary wall once the likely to request epidural analgesia than the less vessel diameter exceeds 150% of that of the affected 'controls'. IL-6 probably has a role in white blood cell. Then, due to low-affinity adhethese temperature differences. Another study has sive interaction between leukocytes and vascular demonstrated a relation between foetal IL-6 and endothelium on the one hand, and to the force maternal serum IL-6 levels, suggesting a mater-of blood flow on the other hand, leukocytes start nally induced modification of foetal immune to roll. In inflamed tissue, leukocyte rolling frefunction and stress response. 47 IL-6 measured in quently leads to a stationary state in which the plasma seems to be a biochemical marker of leukocyte remains firmly attached to the endohuman preterm labour. 48 thelial surface for more than 30s. These leukocytes can then leave the postcapillary venule by Tumour necrosis factor. Tumour necrosis extending pseudopodia between apposing endofactor 49 is mainly produced by macrophages after thelial cells, entering the subendothelial space stimulation by endotoxin and some cytokines. It and the adjacent interstitial compartment. 5 promotes PGE2 and collagenase production by The basis for a selective appearance of differfibroblasts, induces production of other cytoent white cell types in association with different kines such as IL-1, IL-6 and IL-8, is directly cyto-inflammatory reactions (cervicitis) is thought to toxic and is a direct stimulus for PMN respiratory be due to the production and release of unique burst, chemoattractants at the site of inflammation, as well as to the presence and the number of spe-Interleukin-8. Interleukin-8 is a strong chemocific receptors for these individual chemoattactic agent for PMNs but not for blood monotractants on selected cell types. cytes, a weak inducer of the respiratory burst 5 Leukocyte-endothelial cell adhesion is mediand a poor stimulator of elastase secretion by ated by glycoproteins that belong to the selectin PMNs.5This suggests that chemotactic migration family of cell adhesion receptors. L-selectin is and the release of proteases by PMNs may be constitutively present on leukocytes, E-selectin is unrelated phenomena. IL-8 is produced by several upregulated on the endothelial surface of postcell types including macrophages, fibroblasts, capillary venules by cytokines and P-selectin is chorion cells, decidual cells,Samnion cells, 16 and present on activated endothelium and platelets. 5 hepatocytes, when appropriately stimulated by Each type of selectin possesses its own receptor, members of the cytokine network, such as IL-1, however all these ligands are not yet clearly TNF and endotoxin. In contrast to IL-8, neither defined. Selectins participate in rolling, whereas TNF nor IL-1 seem to be directly chemotactic, firm adhesion is possible by the interaction of In contrast to the normal and stable plasma ILintegrins and their ligands. 54 8 levels during pregnancy and labour,  Circulating neutrophils are in the resting state in amniotic fluid increase during gestation.
if there is no systemic inflammation, but they Infection and labour pain may trigger the procontain ]3-integrin molecules constitutively on duction of IL-8 both at term and at preterm their surfaces. After PMN stimulation, these delivery. 4'5 In preterm labour, the IL-8 level in receptors are rapidly induced into a high state of amniotic fluid is a more accurate predictor of avidity that promotes firm adhesion. At the same histologic chorioamnionitis, tocolytic efficacy and time, adhesomes, which contain integrins, fuse with the plasma membrane, resulting in upregutice that myometrial contractions contribute lation of extracellular matrix receptors, mechanically to cervical dilatation. Lumbar epi-Since rolling leads to intimate contact between dural analgesia transiently reduce uterine conneutrophils and endothelial cells, this process tractility, but the rate of cervical dilatation is not should allow neutrophils to become activated by affected. 1'59'6 This underscores the relative indeagents expressed on the endothelial cell surface pendence of both processes and the clinically or by substances released from cells lying imme-negligible effect of epidural analgesia on the diladiately outside the vasculature. These agents tation of the cervix. include PAF and oxygen radicals. Interestingly, The connective tissue of the cervix is comneutrophils with impaired L-section are able to posed of collagen, elastin, numerous fibroblasts adhere and emigrate during stasis, possibly and relatively few smooth muscle cells, separated bypassing the need for selectin for neutrophil by ground substance, which form a strong adherence during uterine contractions, barrier against foetal loss and ascending bacterial Endothelial cells (EC) can be stimulated 55 by infection. 1 An increase in vascularity, water hydrogen peroxide, thrombin and histamine. This content and extensive changes in the connective leads to the transport of Weibel Palade bodies, tissue are responsible for clinically recognized which contain P-selectin. Hydrogen peroxide can cervical softening, effacement and dilatation are induce PAF formation on the EC surface. PAF is encountered as pregnancy progresses. Near term, translocated to the membrane but not released.
PMN and macrophages invade cervical connective This transient co-expression of P-selectin and PAF tissue, 28 leading to a local inflammation deleads to more efficient granulocyte stimulation, scribed as 'cervicitis'. and may also lead to cytokine secretion by adhering monocytes. Thus EC stimulation is a fast, Ground substance: Proteoglycans form the main receptor-synthesis-independent response occurcomponent of the ground substance. They are ring within minutes, leading to leukocyte adher-made up of several glycosaminoglycans (GAGs) ence without obligatory PMN activation, connected to a protein core. These GAGs Endothelial cells can be activated 56 by endocontain a large number of sulphate groups and toxin and cytokines such as TNF, IL-1 and IL-8, are arranged around the collagen fibrils. Their leading to de novo expression of E-selectin and function is not well understood, but they modify adhesion molecules including the endothelial the physical properties of collagen and determine leukocyte adhesion molecule ELAM-1 (with a the water content of the cervix. Hyaluronic acid peak at 4-6 h after stimulation). PAF may also is an important GAG and is associated with the serve as a necessary cofactor, whereas IL-8 may capacity of tissue to retain water. Compared to also act as a secondary signalling agent. Shedding other GAGs, it binds least strongly with collagen, of ELAM-1 (soluble ELAM-1) serves as a conven-and thus will act to destabilize the collagen tional neutrophil chemoattractant. After binding fibrils. Just before labour, the concentration of its neutrophil ligand, ELAM-1 recruits participa-GAGs increases due to increased synthesis, and tion of additional adhesion molecules by trigger-during the active phase of labour a decrease in ing the activation of integrins on the surface of cervical proteoglycans is noted. 62 This drop neutrophils, all of which participate in diapedesis, results in a facilitation of collagen breakdown As the number of PMNs and macrophages in and an increase in cervical water content. Oxythe near-term cervix increase spectacularly, 2'28 the radicals can elicit the breakdown of ground subcascade mechanisms eliciting tissular white blood stance proteins including hyaluronic acid, 6 cell recruitment and activation as described whereas PMN-derived enzymes for ground subabove must be activated before and during stance degradation include cathepsins, elastase delivery. The result of these processes is the and lysozyme. To make it even more complibenign softening and dilatation of the cervix, as a cated, soluble hyaluronic acid can induce the result of local macrophage and PMN activations production of some cytokines including TNF 64 permitting the passage of the foetus, and IL-1,65 and can inhibit oxygen radical formation and phagocytosis by macrophages. Cervical ripening Collagen: Cervical collagen, 70% type I and 30% In sheep, cervical division of the cervix from type III, 6 is resistant to most extracellular prothe rest of the uterus still resulted in cervical teases, except collagenase and PMN or macroripening during labour, suggesting that both phage elastase. During pregnancy, mature processes can occur relatively independently. 57 collagen, with many cross links is broken down Cervical PGE2 production increases 58 in response and replaced with new collagen which is more to stretching and it is known from clinical prac-amenable to rapid breakdown at the time of parturition. The amount of intact collagen sine 3'5'-cyclic monophosphate (cGMP). It inhidecreases 70% in comparison with concentra-bits leucocyte adhesion to endothelial cells 75 and tions in the non-pregnant cervix. 7 Local cervical the production of endothelin. 7 NO is synand plasma collagenase enzyme activity is thesized from the ,-arginine molecule, a reaction mammal during the active second phase of that is catalysed by the enzyme NO-synthase, 74 labour. This collagenase found during labour is leaving citrulline as a stable marker of NO synsynthesized by cervical PMNs, and to a lesser thesis. Nitrite and nitrate are stable end-products degree, by cervical fibroblasts.* It is released as of NO metabolism. A first subtype of NO-synthase a latent procollagenase, which in turn has to be is a constitutive, cytosolic calcium-dependent cleaved by another protease before it is active, enzyme, releasing NO after direct stimulation Tertiary granules of PMNs contain gelatinase, with calcium ionophores, acetylcholine, bradywhich hydrolyses denatured collagen and breaks kinine, lipopolysaccharide, thrombin, PAF and down laminin and fibronectin. This enzyme electrical stimulation. 74'77 A second subtype of increases consistently with the influx of PMNs.
NO-synthase is an inducible Ca-independent Interestingly, serum collagenase levels are higher enzyme which is found following cellular contact in parturients with ripe cervices who go into with cytokines. This upregulation is strongly preterm labour than in women with unripe cer-inhibited by many agents including glucocortivices who deliver at term. 9 coids, IL-4 and IL-10. 23;78 In rodents, NO is produced by nerves, blood Elastin: The synthesis and degradation of elastin cells and decidual cells during gestation.  is not well understood, 7 but PMN-derived tissue Nitrate, a stable NO metabolite, plasma cGMP elastate levels gradually increase during preg-and urinary cGMP are increased in the gravid nancy, and double again during labour. Morerat. 82 At the end of gestation and during over, PMN-derived elastase can degrade virtually labour, NO production and the sensitivity of all extracellular matrix 2roteins, including col-smooth muscle to NO is substantially reduced, lagen and proteoglycans, which suggests that NO may contribute to the In summary, as labour progresses, the increase maintenance of uterine quiescence, maternal in proteases outpace the local content of enzyme vasodilatation and uterine immune suppression inhibitor, leading to a net degradation of conduring gestation but not during labour. 79-m nective tissue. The major sources of oxygen Administration of an inhibitor of NO-synthase radicals and proteases are PMNs and macro-caused hypertension and growth retardation, but, phages which in their turn are attracted and acti-the gestational duration was not affected. 8 vated by cytokines. Hormones and prostaglandins In humans, constitutive NO-synthase is expresalter the sensitivity of these cells to several cyto-sed by the syncytiotrophoblast, and inducible kines. For example, prolactin increases phago-NO-synthase can be present on placental chorcytosis by PMN and macrocytes, 7 possibly ionic villi and the basal plate of the human leading to accelerated normalization of the cervix uterus. 4 The role of NO during gestation and postpartum, labour in humans remains to be determined.

Labour
Identification of hormone receptors, e.g. the oxytocin receptor, and the discovery of regulatory intracellular proteins, helped to clarify the mechanism of the action of relaxing and contracting substances on the myometrium. No studies However, in a small study, transdermal nitrates, which are potent NO sources, seem to inhibit premature labour. 85 Hormones, prostaglandins and the immune system Hormones and prostaglandins are necessary on the direct effects of cytokines on uterine for delivery. Their role during parturition is sumsmooth muscle cells have been published yet. marized below, especially with respect to the TNF and IL-1 stimulate the production of endoimmune system. thelins, which are potent uterotonics secreted by amnion and endothelial cells, and these cytokines Oestrogens: The foetus supplies the placenta promote the production of several prosta-with precursors for oestrogen synthesis, and glandins, w Endothelins stimulate the production oestrogens are then released into the maternal of arachidonic acid by monocytes or macro-circulation. Maternal serum levels of oestrogens phages. 72'7 gradually increase during normal pregnancy. Substances known to augment oestrogen syn- The role of nitric oxide: Nitric oxide (NO) 74 thesis include intracellular cAMP, human chorrelaxes smooth muscle cells by elevating guanoionic gonadotropin (hCG), ACTH and insulin, whereas glucocorticoids attenuate oestrogen iban, an oxytocin antagonist, decreased the conproduction, traction frequency in patients in preterm labour, Oestrogens are thought to be essential in the oxytocin appears to play a role in the mainpreparation, rather than the mechanism, of the tenance of contractions in these women. 9 initiation of birth. In sheep, oestrogens enhance oxytocin responsiveness of the uterus, cause pre-The cytokine-neuroendocrine interaction: The mature parturition, stimulate myometrial activity, effects of cytokines on the neuroendocrine increase intracellular calcium and the myometrial system are complex. 91 The major site of produccontent of proteins involved in contraction, tion of cytokines is the locus of inflammation, increase a-and reduce I-adrenergic receptor viz. the cervix. The cytokines can have their content, stimulate prostaglandin production and effect either locally, called a paracrine effect, or reverse the inhibitory effects of progesterone, at a distance, called an endocrine effect. For Oestrogens can modulate the synthesis of glyco-example, endotoxin or low plasma levels of aminoglycans and can increase the collagen turn-some cytokines have an effect on the hypothalaover in the uterus. However, conflicting results mus and the pituitary gland. 92 Nevertheless, little on the efficacy of oestrogens with respect to cer-information is available about neuroimmune vical ripening have been reported, s interactions during pregnancy, particularly about the influence of stress and pain during labour on Progesterone.. Progesterone production by the this neuroimmune function. corpus luteum starts early in pregnancy. There-The hypothalamic-pituitary-adrenal axis is after, progesterone is synthesized by the trophostimulated by IL-1, TNF and to a lesser degree ILblast. Its production increases with placental size, 6, mainly via release of corticothrophin-releasing resulting in a rise in maternal plasma concentra-hormone, 9 a direct action on the adrenal gland 94 tion to reach a plateau at about 32 weeks' gesta-and probably also on the pituitary gland. This tion. Placental progesterone production is results in an increased production of glucocortithought to operate maximally and at a rate detercoids. mined by the cholesterol supply from maternal Severe infection and inflammation are frecirculation, hCG, [3-adrenergic agonists and cate-quently accompanied by an inhibition of reprocholamines have little effect on progesterone ductive function. 95 Cytokines such as IL-1 and synthesis. 87 TNF depress the hypothalamic-pituitary-gonadal Progesterone can restrict rises in intracellular axis via the hypothalamus (gonadotrophin-releascalcium, restrict the coupling efficiency of [1ing hormone), the pituitary (LH, FSH) and the r 96 adrenergic receptors to enhance cAMP producovary (ste oidgenesis). Administration of IL-1 tion, or inhibit uterine prostaglandin production, leads to increased oxytocin levels and increases, The 'progesterone withdrawal' hypothesis with at least in vitro, the uterine myometrial response concomitant oestrogen secretion was based on to oxytocin. However, it should be noted that in the dramatic decrease in plasma levels of progescontrast to IL-6, neither TNF nor IL-1 are found terone just before parturition in several mamma-during normal parturition into the patients' lian species. In humans, however, no reduction serum. of plasma progesterone has been observed Glucocorticoids and oestrogens 97 can exert a before the onset of labour. On the other hand, negative effect on the immune system, because inhibition of progesterone synthesis or surgical they inhibit the synthesis of IL-1, TNF, IL-2, IL-6 progesterone withdrawal result in abortion or and IL-8 by macrophages. Progesterone is a 98 increased sensitivity of the myometrium to utero-potent anti-inflammatory agent. Antiprogestins tonic agents, ameliorate cervical ripening, as these agents 99 promote PMN influx, probably as a result of Oxytocin: Oxytocin promotes the production of a neutralization of an inhibitory effect of proprostaglandins <s9 by a protein kinase C depengesterone on IL-8 production by choriodecidual dent mechanism, and oxytocin administration cells. 14 induces labour in near term parturients.
However, plasma oxytocin concentrations do not Prostaglandins.. Some prostaglandins given by increase initially during labour, and oxytocin mouth, intravenously or by cervical instillation, does not induce myometrial gap junctions or evoke myometrial contractions, cervical ripening cervical ripening. Plasma oxytocin levels do not and abortion or delivery at any stage of pregincrease until late in parturition, so the increase nancy. Inhibitors of prostaglandin synthesis of membrane oxytocin receptors by an unknown lengthen the induction-abortion time interval mechanism upregulates the effects of oxytocin after instillation of hypertonic saline, or lead to during the second stage of labour. 89 Since antox-prolongation of gestation.
Arachidonic acid in tissue is present in an esterified form in glycerophospholipids, which form 10 to 30% of the total fatty acid content of the (intra)uterine tissues. The formation of free arachidonic acid is considered to be a rate-limiting stop in prostaglandin synthesis. In some tissues, however, the rate of prostaglandin production is at least partially regulated by the rate of conversion of arachidonic acid to prostaglandins. 8 Moreover, not all arachidonic acid is necessarily directed toward prostaglandin and prostanoid biosynthesis, because a significant proportion of it may be converted by lipoxygenase to form leukotrienes and hydroxyeicosatetraenoic acids, by epoxygenase to form epoxides and, more importantly, to reincorporation in the structural fat of cell membranes. During the production of prostaglandins from arachidonic acid, oxygen radicals are formed. These radicals can influence the cyclooxygenase enzyme, altering PG formation. 29'3 Two genes, for cyclooxygenase, termed cox-1 and cox-2, have been cloned and expressed in functional form. The cox-1 gene is expressed ubiquitously in vivo and in vitro, whereas the cox-2 gene is expressed at very low levels in normal tissues. The expression of the cox-2 gene is induced by lipopolysaccharide or IL-1. The cyclooxygenase undergoes irreversible self-inactivation, so that modulation of activity depends on continued synthesis of the enzyme, lm Intrauterine bacterial inoculation in mice led to preterm delivery, accompanied by induction of ribonucleic acid transcript for several cytokines and for cox-2.18 Cox-2 knockout mice are infertile, which may at least in part be related to the important role which prostaglandins play in implantation, pregnancy and lactation. 2 Bacterial toxins, particularly IL-1, TNF and IL-6, in concentrations found in amniotic fluid during parturition, 1 increase prostaglandin formation by amnion cells and chorion laeve cells (PGE2, PGFaz), 12 endometrial stromal cells which are the progenitors of the decidual cells (PGF2a, PGE2) 13'14 and myometrial muscle cells (PGI2, PGE2 and PGF2). 9 Other cytokines, such _as IL- 105 43 106 4 and transforming growth factor-132 suppress prostaglandin production by monocytes. Therefore, infection as a causative event of labour has led to the theory that part of the problem of prematurity is a problem of infection. 1'11'17 Some studies indicate a modulating effect of prostaglandins on immune cells with respect to cytokine production, or response threshold to some cytokines. 14 Recently, uteroglobulin (Clara Cell protein, CCl0, protein 1) is found in abundance in amniotic fluid ma and probably originates from the foetal lung. It has potent anti-inflammatory properties by inhibiting tl 109 phospholipase A2 and PAF genera 'on; however, its exact role in parturition is under investigation.

Conclusion
The physiology of parturition is at least partially explained by the contribution of the immune system. Several cascades seem to play a role, but no pathway is totally independent. Before therapeutic intervention aimed at modulating one or more cascades to reduce cervical ripening and thus to prevent prematurity can be considered, one must be certain of the side effects of such therapy. For example, antibodies against ELAM will dramatically reduce PMN invasion of the cervix, inhibiting cervical softening of dilatation. However, the resistance of the mother against bacterial invasion will be reduced simultaneously, leading to bacteraemia with potentially disastrous effects on both the mother and foetus.
Extensive research is necessary to understand the pathophysiology of parturition to allow appropriate interference with these physiological pathways. Moreover, the pathophysiological backgrounds of several gestationally related diseases, including haemolysis, elevated liver enzymes, low platelet or HELLP syndrome, (pre)eclampsia or recurrent abortion, need to be unravelled. Further research to determine the effects of analgesia and anaesthesia on this immuno-obstetric system will also identify more accurately the hazards or benefits of these techniques on foetal and maternal well-being.