Increased expression of interleukin-1 receptor type 1 in active endometriotic lesions.

The establishment and progression of ectopic endometrial implants are dependent upon their interaction with and responsiveness to the stimuli present in their new environment. According to our and other previous studies, immune cells-derived cytokines, such as IL-1, may alone or in concert with estrogens, enhance the capability of ectopic endometrial cells to implant and develop into the host tissue. In the present study, immunohistochemical and dual immunofluorescence analyses showed that the functional signaling interleukin-1 receptor type 1 (IL-1RI) is expressed in endometriotic tissue, particularly in the glands, and identified endothelial cells, macrophages, and T-lymphocytes as cells having marked expression of IL-1RI. The highest concentrations of IL-1RI protein in endometriotic tissue, as evaluated using histological score (HSCORE) and measured by ELISA, were found in red endometriotic lesions as compared with typical black-blue or white lesions. Western blotting showed a significant increase in the levels of the 50 kDa band, whose apparent molecular weight corresponds to the soluble form of IL-1RI. RT-PCR analysis of IL-1 mRNA levels showed a pattern of expression comparable to that of the protein. Interestingly, IL-1RI expression was more significant in the proliferative than in the secretory phase of the menstrual cycle. Marked expression of IL-1RI, the functional signaling receptor that mediates cell activation by IL-1, in red endometriotic implants, which are highly vascularized and represent the earliest and most active forms of the disease, point to a higher cell receptivity for IL-1 in these lesions, a relationship with the activity of the disease and a possible involvement in the early steps of endometriotic tissue growth and development.

Cycle-dependent expression of macrophage migration inhibitory factor in the human endometrium.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that was shown to promote angiogenesis and tissue remodelling. Our previous studies identified MIF as one of the principal bioactive molecules involved in endothelial cell proliferation released by ectopic endometrial cells. METHODS AND RESULTS: In the present study, we examined the expression of MIF in the human endometrium and found an interesting distribution and temporal pattern of expression throughout the menstrual cycle. Immunoreactive MIF was predominant in the glands and surface epithelium. Dual immunofluorescence analysis further identified endothelial cells, macrophages and T-lymphocytes as cells markedly expressing MIF in the stroma. Quantitative assessment of MIF protein showed a regulated cycle phase-dependent expression pattern. MIF expression increased in the late proliferative/early Secretory phase of the menstrual cycle was moderate during the receptive phase or what is commonly called the implantation window before increasing again at the end of the cycle. This pattern paralleled MIF mRNA expression determined by northern blot. CONCLUSION: The cycle phase-specific expression of MIF suggests a tight regulation and perhaps different roles for this factor in the reparative, reproductive and inflammatory-like processes that occur in human endometrium during every menstrual cycle.

Cycle-dependent expression of interleukin-1 receptor type II in the human endometrium.

Cytokines such as interleukin-1 (IL-1) play a major role in the reparative and inflammatory-like processes that occur in human endometrium during every menstrual cycle, but they also seem to be implicated in critical reproductive events such as ovulation and implantation. Interleukin-1 is tightly regulated in the body by a complex network of control systems. In the present study, we examined the expression of IL-1RII, a natural specific inhibitor of IL-1, in the human endometrium and found an interesting distribution and temporal pattern of expression throughout the menstrual cycle. Immunoreactive IL-1RII was found in stromal as well as epithelial cells, but it was predominant within the lumen of the glands and the apical side of surface epithelium. In situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) analyses showed higher levels of mRNA in epithelial than in stromal cells. The IL-1RII cellular and luminal secretion followed a regulated cycle phase-dependent pattern of expression. Although elevated in the late proliferative/early secretory phase of the menstrual cycle, IL-1RII luminal secretion significantly decreased in the midsecretory phase, reaching its lowest levels at Day 21, before augmenting markedly again during the late secretory phase. This pattern of expression was less obvious at the level of cellular staining, as examined by immunohistochemistry, but it was corroborated by Western blot analysis of IL-1RII protein and semiquantitative RT-PCR of IL-1RII mRNA in the whole endometrial tissue and separated glandular epithelial cells. The reduced expression of IL-1RII within the implantation window suggests the existence of accurate regulatory mechanisms that, by down-regulating IL-1RII expression, alleviate IL-1 inhibition during this crucial period and facilitate IL-1 proimplantation actions. The elevated expression of IL-1RII observed during the late secretory phase suggests an involvement of IL-1RII in control of the proinflammatory state that takes place in the endometrium during the premenstrual and menstrual periods.