Expression and function of leukemia inhibitory factor and interleukin-6 genes during porcine pregnancy

The hematopoietic cytokines, leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), are signaling molecules present in the uterine luminal fluid of many species, which are developmentally synthesized and secreted by maternal and embryonic tissues. LIF is essential for implantation in the mouse, as well as for differentiation of the embryonic inner cell mass. LIF and IL-6 modulate the biosynthesis of various proteinases and their specific inhibitors. Antileukoproteinase (ALP) is a proteinase inhibitor coexpressed with hematopoietic cytokines in porcine endometrium and placenta. It is expressed most abundantly in uterine endometrium of species with epitheliochorial placentation, as opposed to the species exhibiting endotheliochorial or hemochorial placentation. Thus, ALP has been proposed to protect endometrium from erosion by conceptus-elicited proteinases. We examined by RT-PCR the temporal expression of LIF and IL-6 cytokine genes as well as that encoding the cytokine-binding subunit of the LIF receptor (LIFR-{dollar}beta{dollar}) in the porcine female reproductive tract during pregnancy. The highest amounts of LIF, LIFR-{dollar}beta{dollar} and IL-6 mRNAs were found in endometria and placentae during the early post-implantation period, suggesting a potential role for these cytokines in feto-maternal developmental events. IL-6 mRNA was expressed in the Jag-1, cell line derived from day 14 porcine trophoblast, suggesting a potential role for IL-6 in implantation of pig blastocysts. LIF mRNA was most abundantly expressed in day 30 placentae, whereas LIFR-{dollar}beta{dollar} mRNA abundance was greatest in the corresponding endometrium, suggesting the involvement of LIF as a signaling molecule at the feto-maternal interface. We examined by Northern dot-blot analysis the in vitro effects of hrLIF and hrIL-6 on the expression of ALP mRNA in pregnant porcine endometrium. The treatments of day 12 endometrial explants with hrLIF, as well as with hrIL-6, resulted in increased ALP expression. The stimulatory effects of LIF and IL-6 indicate that a post-implantation role for these cytokines may be to determine the degree of endometrial erosion by the conceptus, as mediated by the cytokine-induced proteinase inhibitors. These findings indicate that LIF and IL-6 may have a role in feto-maternal signaling, such as regulation of placentation.