Aberrant expression of interleukin-6 and its receptor in Fallopian tubes bearing an ectopic pregnancy with and without tubal cytomegalovirus infection

Abstract

Cytomegalovirus (CMV) has recently been suggested as a potential risk factor for the development of ectopic pregnancy (EP) following upper genital tract infection in women. However, little is known about its associated underlying pathogenic mechanisms. This was a prospective case-control study that measured the prevalence of CMV infection in Fallopian tubes (FT) bearing an EP and its effects on the tubal expression of interleukin (IL)-6 and its signaling molecules, which are known to play significant roles in the immune response against CMV infection as well as embryo implantation. Fresh FTs from 96 EPs during salpingectomy and another 61 women at the midluteal phase during total abdominal hysterectomy (TAH) were collected to measure the rate of CMV by an IVD CE PCR kit. The participants were then classified to measure the expression of IL-6, its receptor (IL6R) and intracellular mediators (gp-130, STAT3) by immunohistochemistry and quantitative RT-PCR. The results showed significantly higher (P = 0.01) rates of CMV in FTs obtained from EP (22.9 %) compared with controls (8.2 %). IL-6 (P = 0.003), IL6Rα (P = 0.02), gp 130 (P = 0.008) and STAT3 (P = 0.03) were significantly higher in TAH-positive (n = 5) compared with TAH-negative FTs by immunohistochemistry. Furthermore, the expression in the non-infected EP samples was significantly higher for IL-6 (P = 0.004), IL6R (P = 0.007), gp130 (P = 0.006) and STAT3 (P = 0.007) compared with negative TAH. Similar results were observed by quantitative PCR. CMV-positive EP samples showed the highest significant increase of the studied molecules by all techniques. In conclusion, Fallopian tubal infection with CMV is higher in EP and could predispose to embryo implantation by up-regulating the expression of IL-6 and its related molecules as part of tubal innate immune response. Further in vitro and in vivo studies are compulsory to illustrate the roles of IL-6 and CMV in the pathogenesis of EP.

Keywords: Cytomegalovirus; Ectopic pregnancy; Embryo implantation; Endometrial receptivity; Fallopian tube; IL-6.

Fig. 1

Immunohistochemistry localisation of IL-6 (left column) and IL6Rα (right column), in tubal samples collected from midluteal phase of the cycle and negative for CMV (a, b), midluteal phase samples positive for CMV (c, d), EP negative for CMV (e, f) and EP positive for CMV (g, h) groups. (×400 magnification, scale bar = 5 µm)

Fig. 2

Immunohistochemistry localisation of gp 130 (left column) and STAT3 (right column), in tubal samples collected from midluteal phase of the cycle and negative for CMV (a, b), midluteal phase samples positive for CMV (c, d), EP negative for CMV (e, f) and EP positive for CMV (g, h) groups. (×400 magnification, scale bar = 5 µm)

Fig. 3

Mean ± SD of messenger RNA relative expression of (a) IL-6, (b) IL6RA, (c) gp130 and (d) STAT3 in Fallopian tube samples collected from midluteal phase of the cycle and negative for CMV (NC), midluteal phase and positive for CMV (PC), EP negative for CMV (N-EP) and EP positive for CMV (CMV-EP) groups. (a = P < 0.05 compared with NC, b = P < 0.05 compared with PC and c = P < 0.05 compared with N-EP groups)