ABSTRACT
Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-α (IL-7Rα)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Rα leads to increased soluble IL-7Rα production. Given the functional interaction between sIL-7Rα, membrane-bound IL-7Rα and IL-7, we assessed IL-7, mIL-7Rα and sIL-7Rα levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Rα levels compared with 73 HCs. The levels of sIL-7Rα increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Rα could result in a higher mIL-7Rα to soluble IL-7Rα ratio. Indeed, 52 MS patients had significantly increased mIL-7Rα to sIL-7Rα ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Rα influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Rα ratio. The soluble IL-7Rα levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Rα level may influence responsiveness of IL-7Rα(+) cells.
Subject(s)
Interleukin-7/metabolism , Multiple Sclerosis/genetics , Receptors, Interleukin-7/genetics , Adult , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Case-Control Studies , Female , Heterozygote , Humans , Interleukin-7/blood , Male , Polymorphism, Single Nucleotide , Receptors, Interleukin-7/blood , Receptors, Interleukin-7/metabolism , SolubilityABSTRACT
In the mammalian ovarian follicle maturing oocytes are nurtured and supported by surrounding somatic cells, the mural granulosa cells and the cumulus cells. These cells are regulated by follicle-stimulating hormone (FSH), originating from the pituitary, and paracrine factors derived from the oocyte. To gain insight into the mechanisms involved in the regulation of granulosa cell function, this study aimed to identify genes in mural granulosa cells that are regulated by FSH and oocyte secreted factors using the pig as a model organism. Mural granulosa cells were collected from 3-6 mm follicles from sow ovaries and cultured in serum free medium in the presence or absence of FSH and/or isolated cumulus oocyte complexes (COCs). FSH significantly increased both the metabolic activity and progesterone production of granulosa cells, while the presence of COCs reversed these FSH effects. Expression levels of mRNA in the absence/presence of FSH and COCs were analyzed on porcine specific microarrays representing 11,300 genes. Both previously identified and novel FSH target genes as well as some oocyte affected genes were found. Expression of inhibitor of DNA binding protein 2 and 3, ID2 and ID3, was decreased by FSH but increased by COCs, as validated by quantitative PCR. These proteins function as dominant negative basic helix loop helix (bHLH) transcription factors and since all regulated genes contain the consensus E-box sequence that can bind bHLH factors, our data suggest that FSH and COCs may regulate granulosa cell function by tuning the activity of bHLH factors, through ID2 and ID3.
Subject(s)
Cell Communication/physiology , Follicle Stimulating Hormone/pharmacology , Granulosa Cells/drug effects , Oocytes/physiology , Swine/genetics , Animals , Cell Communication/genetics , Cell Survival/drug effects , Cell Survival/physiology , Cells, Cultured , Coculture Techniques , Female , Gene Expression/drug effects , Gene Expression Profiling , Genes/physiology , Granulosa Cells/metabolism , Granulosa Cells/physiology , Microarray Analysis , Oogenesis/drug effects , Oogenesis/genetics , Oogenesis/physiology , Swine/metabolism , Swine/physiologyABSTRACT
BACKGROUND: Disease activity in patients with multiple sclerosis (MS) is suppressed during pregnancy, whereas attack frequency increases after delivery. It is yet unclear, which immuno - endocrinological processes mediate these disease fluctuations. Leptin has been identified as a hormone that can influence inflammatory activity. OBJECTIVE: The aim of this study was to investigate whether pregnancy-induced fluctuations of serum leptin levels differed between patients with MS and controls and whether serum leptin levels correlate with periods of enhanced and diminished disease activity. METHODS: Women with MS and healthy women were prospectively followed during and after pregnancy. The MS group could be studied already at a timepoint before pregnancy. Serum leptin and soluble leptin receptor (SLR) levels were measured using enzyme-linked immunosorbent assay. RESULTS: Pre-pregnancy serum leptin levels were (mean +/- SD) 22.9 +/- 12.8 ng/ml in the MS group. These levels increased in the third trimester to 28.5 +/- 15.0 ng/ml (P = 0.007). The third trimester serum leptin levels in healthy women were comparable, 29.4 +/- 19.0 ng/ml. Serum leptin levels after delivery dropped to 18.5 +/- 12.8 ng/ml in women with MS (P < 0.001) and to a lesser extend (22.0 +/- 17.5 ng/ml) in healthy women (P = 0.04). SLR levels showed the same pattern. Remarkably, women with the highest relative decrease in serum leptin levels after delivery had more often a postpartum relapse (P = 0.008). CONCLUSION: In women with MS, leptin increased during late pregnancy. A postdelivery drop in leptin levels was observed in both the MS and control group. The postdelivery drop was associated with the occurrence of postpartum relapse.
