Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 ...Finns we identified 27 genome-widely significant loci (p < 1.2 × 10−9) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Activities of prolyl hydroxylase (PH), lysyl hydroxylase (LH), and the collagen glycosyltransferases and the extent of the posttranslational modification of lysine residues in newly synthesized ...collagen were studied in fibroblast cultures obtained from 9 seleroderma patients. The rate of procollagen synthesis had increased more than 3-fold in 3 scleroderma fibroblast lines, but had not changed to the same extent in the others, even though these did not differ from the “high-producers” histologically, clinically, or immunohistologically. The activities of PH and LH correlated significantly with the rate of procollagen synthesis in the same cell lines (p < 0.001), but the glycosyltransferase activities were not elevated in the scleroderma fibroblasts. Further studies nevertheless indicated that the extent of the posttranslational modification of lysine residues had not significantly changed in the procollagen synthesized by any of the scleroderma fibroblasts investigated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The steroid modulation of collagen metabolism was studied by injecting chick embryos with dexamethasone in vivo, and collagen synthesis was subsequently assayed by pulse-labeling the tissue with ...14Cproline in vitro. The synthesis of 14Chydroxyproline in tendons and sterna from chick embryos treated with dexamethasone was markedly reduced as compared with untreated controls. The inhibition of 3Hhydroxyproline synthesis was accompanied by a similar reduction in type I and II procollagen mRNA levels, as detected by Northern blot and dot blot hybridizations with chick pro alpha 1(I), pro alpha 2(I) and pro alpha 1(II) sequence specific cDNAs. The reduction in type II procollagen mRNA level was shown to be dose dependent. Control experiments indicated that the post-translational hydroxylation of prolyl residues was only slightly decreased in dexamethasone treated animals, and that the specific activity of the intracellular free proline pool and the intracellular degradation of collagen were unchanged. To address the mechanisms of the inhibition of collagen biosynthesis, specific binding of dexamethasone to glucocorticoid receptors in chick embryo tendon and cartilage cells was studied in a whole cell assay using 3Hdexamethasone as the ligand. Matrix-free tendon and cartilage cells had approximately 19,000 and 15,000 receptor sites per cell, respectively, and the binding affinities (Kd) for dexamethasone in tendon and cartilage cells were 2.9 x 10(-9) and 2.3 x 10(-9) M. Comparable values were obtained using a cytosol binding assay. The nuclear binding of dexamethasone in tendon and cartilage cells were similar. The results suggest that the dexamethasone-induced inhibition of collagen production is primarily due to decreased levels of functional procollagen mRNA, possibly resulting from receptor-mediated inhibition of the gene expression on the transcriptional level.
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