Peripheral blood mononuclear cells stimulate progesterone production by luteal cells derived from pregnant and non-pregnant women: possible involvement of interleukin-4 and interleukin-10 in corpus luteum function and differentiation

Abstract

Human luteal cells have been reported to express human leukocyte antigen-DR and lymphocyte functional antigen-3 on the cell surface, suggesting physiological interaction between luteal cells and T-lymphocytes through the menstrual cycle into early pregnancy. To elucidate the role of peripheral lymphocytes on corpus luteum differentiation, the effect of peripheral blood mononuclear cells (PBMC) on steroidogenesis by luteal cells was investigated. The production of Th-2 cytokines such as interleukin (IL)-4 and IL-10 by the co-cultured cells was also examined, and the effects of these cytokines on progesterone production by luteal cells were investigated. Corpora lutea were obtained from eight non-pregnant women in the luteal phase and five women in early pregnancy for luteal cell culture. PBMC were isolated from unrelated women in the follicular phase, secretory phase, and early pregnancy. After coculture with allogenic PBMC for 48 h, progesterone production was significantly enhanced by PBMC from the secretory phase and early pregnancy in the non-pregnant luteal cell culture. In the pregnant luteal cell culture, a significant increase in progesterone production was also observed by the co-culture with PBMC from women in early pregnancy, showing that PBMC have a luteotrophic effect. The stimulatory effects of PBMC were also observed in co-culture conditions which prevented direct cell-to-cell interaction with luteal cells, showing the minor influence of mixed lymphocyte reaction. By co-culture with PBMC, the production of IL-10, but not IL-4, was significantly augmented in luteal cell culture derived from non-pregnant women, whereas the production of both IL-4 and IL-10 was significantly enhanced in the luteal cell culture derived from pregnant women. Moreover, IL-4 and IL-10 promoted progesterone production by cultured luteal cells, especially in the luteal cell culture derived from corpora lutea of early pregnancy. These findings indicate that PBMC stimulate progesterone production by luteal cells and suggest the involvement of PBMC in corpus luteum function and differentiation probably via the Th-2-type lymphocytes.

Cnr2 Deficiency Confers Resistance to Inflammation-Induced Preterm Birth in Mice

“…In this context, our results showing resistance of Cnr2 Ϫ/Ϫ females to LPSinduced preterm birth point toward an important concept that CB2 signaling is a contributing factor in regulating IL-10 levels and ovarian function after LPS challenge. Indeed, IL-10 was shown to stimulate P 4 production in human luteal cells in vitro (48). In contrast, there is also evidence that inflammation/infection induces proinflammatory cytokines, which causes ovarian luteolysis and drop in serum P 4 levels.…”

Molecular regulators of resolution of inflammation: potential therapeutic targets in the reproductive system

“…Initial influx of neutrophils at ovulation is followed by a delayed monocyte chemotaxis, while a further selective increase in monocyte/macrophage number is observed at luteolysis (Brannstrom et al 1994). In addition, luteal macrophages display a pro-resolution M2-type phenotype characterised by phagocytic activity and Th2 cytokine production (Hashii et al 1998). Macrophages have been proposed as causal in the demise of the corpus luteum, being capable of producing many pro-apoptotic factors including TNF-a.…”

Immune Regulation of Human Embryo Implantation by Circulating Blood Cells

“…We found that PBMC derived from women in early pregnancy promoted progesterone production as much as that by HCG stimulation, suggesting that circulating blood immune cells in early pregnancy enhance CL function (Hashii et al, 1998). Based on these findings, we extended our hypothesis to the further concept that circulating immune cells transmit information about the presence of the developing embryo to various organs throughout the whole body and induce adequate functional change or differentiation in these organs to facilitate embryo implantation (Fujiwara, 2006).…”