CERVICAL RIPENING WITH THE CYTOKINES INTERLEUKIN-8, INTERLEUKIN-1-BETA AND TUMOR-NECROSIS-FACTOR-ALPHA IN GUINEA-PIGS

It has been suggested that the collagenolytic enzymes released from white blood cells which infiltrate the pregnant human uterine cervix at term are responsible for connective tissue changes which take place during the ripening process. Similarly, an infiltration of inflammatory cells occurs in pregnant guinea-pigs either spontaneously at term or at preterm after treatment with the antiprogestin onapristone. The objective of this study was to evaluate the effects of the inflammatory cytokines interleukin 8 (IL-8), interleukin 1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and a combination of IL-1 beta and TNF-alpha, on cervical ripening in guinea-pigs during advanced pregnancy. The cytokines were applied locally (intracervically) in a gel for 2 days and the effects were assessed on the third day by both extensibility measurements and morphological evaluation. IL-8 treatment on days 42 and 43 post coitum (p.c) and on days 48 and 49 p.c. (term: day 67 +/- 3 p.c.) significantly (P < 0.05) increased cervical extensibility at both stages of pregnancy. Although IL-1 beta treatment (days 42 and 43 p.c.) led to a slight increase in cervical extensibility, this effect was not statistically significant. An electron microscope study performed on days 48 and 49 p.c. revealed a pronounced cervical ripening accompanied by the dissolution of collagen fibres, stromal oedema and the infiltration of polymorphonuclear leukocytes in all cytokine-treated groups. The morphological effects of IL-8 and IL-1 beta were indistinguishable from those observed during normal cervical ripening at term. In contrast, TNF-alpha, both alone and in combination with IL-1 beta, brought about a severe inflammatory reaction with a massive infiltration of lymphocytes, macrophages and polymorphonuclear leukocytes at the investigated dose. We conclude that the local application of the inflammatory cytokines IL-8, IL-1 beta and TNF-alpha produces cervical ripening without inducing labour in pregnant guinea-pigs; the morphological effects of IL-8 and IL-1 beta being similar to the physiological cervical ripening. Our data support the view that cytokines, particularly IL-8, may play an important role during physiological, pathological and induced cervical ripening and could be clinically useful as an adjunct to labour and delivery.