Interleukin-6 Is Neither Necessary Nor Sufficient for Preterm Labor in a Murine Infection Model

Abstract

Objective: The aim of this study was to investigate the role of interleukin 6 (IL-6) in a murine model of bacterially induced preterm delivery.

Methods: On day 14.5 of a 19-20-day gestation, female mice underwent one of two interventions. In experiment 1, pregnant right uterine horns were injected at laparotomy with 0.5-20 μg of recombinant human IL-6 (rhIL-6). In experiment 2, IL-6-deficient (IL-6^-/-) and wild-type control (IL-6^+/+) mice underwent intrauterine inoculation with 10⁵ to 10⁸ heat-killed Excherichia coli organisms. Preterm delivery and maternal survival rates were recorded.

Results: In experiment 1, doses as high as 20 μg of IL-6 per mouse resulted in up-regulation of acute phase reactants but did not cause preterm delivery or other adverse maternal or fetal effects. In experiment 2, in bacterially inoculated mice, the absence of matrnal and fetal IL-6 had no effect on preterm delivery rates.

Conclusion: IL-6 was neither sufficient nor necessary for preterm delivery in these murine models.

Keywords

Interleukin 6 mouse model preterm delivery intrauterine infection parturition

References

1. Romero R , Avila C , Santhanam U , Sehgal PB . Amniotic fluid interleukin 6 in preterm labor. Association with infection. J Clin Invest 1990;85:1392-1400.

2. Romero R , Brody DT , Oyarzun E , et al. Infection and labor III. Interleukin-1: A signal for the onset of parturition. Am J Obstet Gynecol 1989;160:1117-1123.

3. Romero R , Mazor M , Sepulveda W , Avila C , Copeland D , Williams J . Tumor necrosis factor in preterm and term labor. Am J Obstet Gynecol 1992;166:1576-1587.

4. Gravett MG , Witkin SS , Haluska GJ , Edwards JL , Cook MJ , Novy MJ . An experimental model for intraamniotic infection and preterm labor in rhesus monkeys. Am J Obstet Gynecol 1994;171:1660-1667.

5. Horn F , Henze C , Heidrich K . Interleukin-6 signal transduction and lymphocyte function. Immunobiology 2000;202:151-167.

6. Houssiau FA , Devogelaer JP , Van Damme J , de Deuxchaisnes CN , Van Snick J . Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 1988;31:784-788.

7. Kawano M , Hirano T , Matsuda T , et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988;332:83-85.

8. Waage A , Brandtzaeg P , Halstensen A , Kierulf P , Espevik T . The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med 1989;169:333-338.

9. Fortunato SJ , Menon RP , Swan KF , Menon R . Inflammatory cytokine (interleukins 1, 6 and 8 and tumor necrosis factor-alpha) release from cultured human fetal membranes in response to endotoxic lipopolysaccharide mirrors amniotic fluid concentrations. Am J Obstet Gynecol 1996;174:1855-1861; discussion 1861-2.

10.

10. Hillier SL , Witkin SS , Krohn MA , Watts DH , Kiviat NB , Eschenbach DA . The relationship of amniotic fluid cytokines and preterm delivery, amnitoic fluid infection, histologic choriamnionitis, and chorioamnion infection. Obstet Gynecol 1993;81:941-948.

11.

11. Greig PC , Ernest JM , Teot L , Erikson M , Talley R . Amniotic fluid interleukin-6 levels correlate with histologic chrioamnionitis and amniotic fluid cultures in patients in premature labor with intact membranes. Am J Obstet Gynecol 1993;169:1035-1044.

12.

12. Yoon BH , Romero R , Kim CJ , et al. Amniotic fluid interleukin-6: A sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morality. Am J Obstet Gynecol 1995;172:960-970.

13.

13. Turhan NO , Karabulut A , Adam B . Maternal serum interleukin 6 levels in preterm labor: Prediction of admission-to-delivery interval. J Perinat Med 2000;28:133-139.

14.

14. Pfeiffer KA , Reinsberg J , Rahmun A , Schmolling J , Krebs D . Clinical application of maternal serum cytokine determination in premature rupture of membranes—Interleukin-6, an early predictor of neonatal infection? Acta Obstet Gynecol Scand 1999;78:774-778.

15.

15. Mitchell MD , Dudley DJ , Edwin SS , Schiller SL . Interleukin-6 stimulates prostaglandin production by human amnion and decidual cells. Eur J Pharmacol 1991;192:189-191.

16.

16. Hirsch E , Saotome I , Hirsh D . A model of intrauterine infection and preterm delivery in mice. Am J Obstet Gynecol 1995;172:1598-1603.

17.

17. Hirsch E , Muhle RA , Mussalli GM , Blanchard R . Bacterially induced preterm labor in the mouse does not require maternal interleukin 1 signaling. Am J Obstet Gynecol 2002;186:523-530.

18.

18. Mussalli GM , Blanchard R , Brunnert SR , Hirsch E . Inflammatory cytokines in a murine model of infection-induced preterm labor: Cause or effect? J Soc Gynecol Invest 1999;6:188-195.

19.

19. Siewert E , Bort R , Kluge R , Heinrich PC , Castell J , Jover R . Hepatic cytochrome P450 down-regulation during aseptic inflammation in the mouse is interleukin 6 dependent. Hepatology 2000;32:49-55.

20.

20. Romero R , Mazor M , Tartakovsky B . Systemic administration of interleukin-1 induces preterm parturition in mice. Am J Obstet Gynecol 1991;165:969-971.

21.

21. Baggia S , Gravett MG , Witkin SS , Haluska GJ , Novy MJ . Interleukin-1β intra-amniotic infusion induces tumor necrosis factor-α, prostaglandin production, and preterm contractions in pregnant rhesus monkeys. J Soc Gynecol Invest 1996;3:121-126.

22.

22. Starnes HF Jr , Pearce MK , Tewari A , Yim JH , Zou JC , Abrams JS . Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol 1990;145:4185-4191.

23.

23. Barton BE , Jackson JV , Protective role of interleukin 6 in the lipopolysaccharide-galactosamine septic shock model. Infect Immun 1993;61:1496-1499.

24.

24. Yoshimoto T , Nakanishi K , Hirose S , et al. High serum IL-6 level reflects susceptible status of the host to endotoxin and IL-1/tumor necrosis factor. J Immunol 1992;148:3596-3603.

25.

25. Hirsch E , Blanchard R , Mehta S . Differential fetal and maternal contributions to the cytokine milieu in a murine model of infection-induced preterm birth. Am J Obstet Gynecol 1999;180(2):429-434.

26.

26. Hirsch E , Muhle RA . Intrauterine bacterial inoculation induces labor in he mouse by mechanisms other than progesterone withdrawal. Biol Reprod 2002;67:1337-1341.

27.

27. Rizzo G , Capponi A , Rinaldo D , Tedeschi D , Arduini D , Romanini C . Interleukin-6 concentrations in cervical secretions identify microbial invasion of the amniotic cavity in patients with preterm labor and intact membranes. Am J Obstet Gynecol 1996;175:812-817.