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Variation in IL-1beta gene expression is a major determinant of genetic differences in arthritis aggressivity in mice.

ABSTRACT: In humans and in animal models, susceptibility to arthritis is under complex genetic control, reflecting influences on the immunological processes that initiate autoimmunity and on subsequent inflammatory mechanisms in the joints. The effector phases are conveniently modeled by the K/BxN serum transfer system, a robust model well suited for genetic analysis where arthritis is initiated by pathogenic Ig. Here, we mapped the genetic loci distinguishing the high-responder BALB/c vs. low-responder SJL strains. After computational modeling of potential breeding schemes, we adapted a stepwise selective breeding strategy, with a whole-genome scan performed on a limited number of animals. Several genomic regions proved significantly associated with high sensitivity to arthritis. One of these regions, on distal chr2, was centered on the interleukin 1 gene family. Quantitation of transcripts of the Il1a and Il1b candidate genes revealed a 10-fold greater induction of Il1b mRNA in BALB/c than in SJL splenocytes after injection of LPS, whereas Il1a showed much less difference. The differential activity of the Il1b gene was associated with a particular sequence haplotype of noncoding polymorphisms. The BALB/c haplotype was found in 75% of wild-derived strains but was rare among conventional inbred strains (4/33 tested, one of which is DBA/1, the prototype arthritis-susceptible strain) and was associated with vigorous Il1b responses in a panel of inbred strains. Inbred strains carrying this allele were far more responsive to serum-transferred arthritis, confirming its broad importance in controlling arthritis severity.

SUBMITTER: Ohmura K

PROVIDER: S-EPMC1194932 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genetic variation is the major determinant of individual differences in leukocyte endothelial adhesion.

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Comparison of gene expression in the intestinal metaplasia in Cdx2/IL-1beta mice vs IL-1beta alone

2016-08-01 | GSE60320 | GEO

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Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke.

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Comparison of gene expression in the intestinal metaplasia in Cdx2/IL-1beta mice vs IL-1beta alone

Project description:Cdx2/IL-1beta mice have less intestinal metaplasia at the squamocolumnar junction thanIL-1beta mice alone. This study was to identify a mechanism for this effect by examining differences in gene expression patterns when Cdx2 is co-expressed. We dissected out intestinal metaplasia nodules from the squamocolumnar junction in Cdx2/IL-1beta mice and Il-1beta mice and measured gene expression on a Mouse Gene 2.0ST Affymetrix array in Oct 2013.

2016-08-01 | E-GEOD-60320 | biostudies-arrayexpress

p38 MAPK regulates IL-1beta induced IL-6 expression through mRNA stability in osteoblasts.

Project description:Osteoblast-derived IL-6 functions in coupled bone turnover by supporting osteoclastogenesis favoring bone resorption instead of bone deposition. Gene regulation of IL-6 is complex occurring both at transcription and post-transcription levels. The focus of this paper is at the level of mRNA stability, which is important in IL-6 gene regulation. Using the MC3T3-E1 as an osteoblastic model, IL-6 secretion was dose dependently decreased by SB203580, a p38 MAPK inhibitor. Steady state IL-6 mRNA was decreased with SB203580 (2 microM) ca. 85% when stimulated by IL-1beta (1-5 ng/ml). These effects require de novo protein synthesis as they were inhibited by cycloheximide. p38 MAPK had minor effects on proximal IL-6 promoter activity in reporter gene assays. A more significant effect on IL-6 mRNA stability was observed in the presence of SB203580. Western blot analysis confirmed that SB203580 inhibited p38 MAP kinase, in response to IL-1beta in a dose dependent manner in MC3T3-E1 cells. Stably transfected MC3T3-E1 reporter cell lines (MC6) containing green fluorescent protein (GFP) with the 3'untranslated region of IL-6 were constructed. Results indicated that IL-1beta, TNFalpha, LPS but not parathyroid hormone (PTH) could increase GFP expression of these reporter cell lines. Endogenous IL-6 and reporter gene eGFP-IL-6 3'UTR mRNA was regulated by p38 in MC6 cells. In addition, transient transfection of IL-6 3'UTR reporter cells with immediate upstream MAP kinase kinase-3 and -6 increased GFP expression compared to mock transfected controls. These results indicate that p38 MAPK regulates IL-1beta-stimulated IL-6 at a post transcriptional mechanism and one of the primary targets of IL-6 gene regulation is the 3'UTR of IL-6.

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Genetic variation of the IL-28B promoter affecting gene expression.

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| S-EPMC3201970 | biostudies-literature

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