Cytokine control in human endometrium

Cytokines within endometrium participate in both menstruation and implantat ion but also contribute to the defence mechanisms of the mucosal epithelium . Endometrium is under the control of steroid hormones, particularly proges terone and, thus, control of cytokines by this steroid is important. Althou gh appreciable numbers of progesterone receptors are not found in endometri al leucocytes, progesterone can modulate cytokines by acting on uterine cel ls expressing the receptor. The NF kappaB pathway is important in the contr ol of cytokine synthesis and can modulate production of chemokines, matrix metalloproteinases and the inducible prostaglandin synthesis enzyme COX-2. NF kappaB activity can be inhibited by progesterone by either stimulating s ynthesis of I kappaB, the molecule that restrains NF kappaB in the cytosol, or after binding to the nuclear receptor, competing with NF kappaB for rec ognition sites on the relevant gene. In this way, progesterone can limit pr o-inflammatory pathways. The major palliatives for endometrial dysfunctions such as menorrhagia and dysmenorrhoea have been the non-steroidal anti-inf lammatory drugs that inhibit prostaglandin synthesis. Prostaglandins have m ajor effects on cytokine production but the direct action of prostaglandin E on leucocytes is not a pro-inflammatory response but is to stimulate inte rleukin 10 and inhibit interleukin 12 synthesis. The likely effect of the n on-steroidal anti-inflammatory drugs is on the cells surrounding the small blood vessels, where a synergistic action between prostaglandin and chemoki ne will induce leucocyte entry and activation leading to lysis of connectiv e tissue and menstruation. At the time of implantation, tight control of cy tokine synthesis is required. Although leukaemia inhibitory factor is essen tial to implantation, the mouse knockout models show that the prostaglandin system is also essential but that there are mutually supportive pathways t hat compensate for the knockout of many cytokines.