Endometriosis and Infertility: A Multi-cytokine Imbalance Versus Ovulation, Fertilization and Early Embryo Development

Endometriosis is tightly linked to infertility which is manifested at very early or more advanced stages of the gestational cycle. Alteration on the production of a great number of cytokines/growth factors can be accused for problems on ovum maturation, fertilization or implantation. Yet, macroscopically these stages are characterized by the inability of conception. A closer look of the cytokinic profile during the conceptional and early gestational cycle could, however, localize the problem and allow a therapeutic approach. In this commentary, going through the cytokine requirement during ovulation, fertilization and the early stages of pregnancy, it became possible to specifically define the harmful endometriosis-induced cytokines for each of the conceptional and early gestational stages. Thus, regulating the levels of interferon-γ and tumor necrosis-α will facilitate ovulation and fertilization, whereas adjusting the levels of interleukin-1β and colony stimulating gactor-1 will facilitate implantation

Serum levels of pro- and anti-inflammatory cytokines in non-pregnant women, during pregnancy, labour and abortion.

Disturbance of the cytokine equilibrium has been accused for many pathological disorders. Microbial infections, autoimmune diseases, graft rejection have been correlated to over- or under-production of specific cytokines which are produced as responder molecules to the various immune stimuli. The sole naturally occurring immune reaction in the organism is developed during the gestational period where, despite the presence of a semi-allogeneic graft, maternal immunoreactivity is driven to support fetal growth. The successful embryo development has been attributed to the important intervention of cytokines where some have been characterized as indispensable and others deleterious to fetal growth. However, the physiological levels of many factors during the gestational process have not been determined. Thus, in the present study we have measured and established the values of IL-1alpha, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, GM-CSF, TNF-alpha and IFN-gamma during all phases of human pregnancy (first, second and third trimester of pregnancy, labour, abortions of the first trimester) as well as in the non-pregnant control state. This is an attempt to assess serum protein concentrations and present the physiological levels of these cytokines at certain time intervals providing thus a diagnostic advantage in pregnancy cases where the mother cannot immunologically support the fetus. Exploitation of this knowledge and further research may be useful for therapeutic interventions in the future

Investigation of intracellular signals generated by γ-interferon and IL-4 leading to the induction of class II antigen expression

Signal transduction plays a vital role in cellular behaviour as cells respond to various stimuli in different ways and utilize diverse pathways for accomplishing their task. Determination of the pathway followed by various cytokines can be achieved using specific inhibitors which include theophylline (TPH), TMB-8 and W7 that hinder calmodulin binding to Ca2+; sphingosine (SPH), H7 and staurosporine that inhibit protein kinase C (PKC) activation; and mevalonate (MEV) or the anti-p21ras antibody which block G-proteins. This study shows that the immunologically important class II antigens in human cells are up-regulated predominately via the same pathway after gamma-interferon (γ-IFN) treatment, whereas murine cells are activated by other signalling routes. Thus, the calcium/calmodulin (Ca2+/Cam) pathway is preferentially selected for human cells whereas the PKC pathway is more often chosen for murine cells. These findings are firmly supported by other reports and show, in addition, a unique action exerted by γ-IFN, since IL-4, another inducer of class II antigen expression, uses different pathways. This diversity of activation reveals the existence of a previously unknown complicated network of intracellular interactions able to regulate the same phenotype or cellular event. As major histocompatibility complex antigens (MHC) or human leukocyte antigens (HLA), are important in immune recognition and response, the results show that for human cells a more coherent method of HLA-DR antigen induction is followed after γ-IFN administration, as calcium participation seems to be the first step in signal transduction. The same T-cell derived lymphokine, however, follows a totally different route when applied to murine cells

The possible anti-inflammatory role of circulating human leukocyte antigen levels in women with endometriosis after treatment with danazol and leuprorelin acetate depot.

BACKGROUND: Endometriosis is defined as an inflammatory condition of the female reproductive tract, a state often associated with infertility and miscarriage. Many exogenously administered factors (treatments) control the disease via as yet unknown pathways. Possible candidate molecules involved in these mechanisms could be the serum-soluble human leukocyte antigens (sHIA) that have been detected in a variety of human body fluids and that are associated with several diseases. AIMS: We here examine how danazol and leuprorelin acetate depot treatments exert their anti-inflammatory action. It is plausible that subtle alterations mediated by these treatments and in relation to sHLA may explain the pathophysiology of endometriosis and provide insights towards new therapeutic protocols. METHODS: Indirect enzyme-linked immunosorbent assay (ELISA), using specific monoclonal antibodies, determined serum-soluble class-I and class-II HLA levels. ELISA readings from treated women were compared with normal healthy subjects. RESULTS: Serum-soluble class-I and class-II HLA levels are statistically significantly lower (P < 0.001) in women with endometriosis than in the control groups. However, danazol but not leuprorelin acetate depot administration augments soluble HLA class I and class II (P < 0.01 and P < 0.001, respectively) to normal levels during the treatment period, an increase that may account for the anti-inflammatory effect and the remission observed. CONCLUSIONS: It is shown that one of the underlying causes of endometriosis may be the lack of both circulating class-I and class-II antigen levels. Danazol administration acts via an induced release of these antigens, whose presence correlates with the degree of the inflammatory alleviation obtained. We thus provide evidence that the inflammatory state of the disease appears to be associated with soluble HLA levels because, 3 months after ceasing therapy, the circulating antigens in the serum return to the same levels that correspond to the pathological condition