Alu elements have repeatedly been found involved in gene rearrangements in humans. Although these elements have been suggested to stimulate gene rearrangements, sparse information is available for the possible mechanism(s) of these events. Here we present a compilation of Alu elements that have been involved in recombinational events leading to gene rearrangements, indicating the presence of a common 26 bp core sequence at or close to the sites of recombination. Besides the obvious possibility of retrotransposition, gene rearrangements may be induced by sequences that stimulate genetic recombination. We suggest that the core sequence stimulates recombination and may thereby cause the frequent involvement of these elements in gene rearrangements. Curiously, the core sequence contains the pentanucleotide motif CCAGC, which is also part of chi, an 8 bp sequence known to stimulate recBC mediated recombination in Escherichia coli.
The expression of both IL-12 and IL-17 mRNA is induced in active UC and CD and may thus be involved in sustaining the intestinal inflammation in IBD. Inhibition of IL-12 or IL-17 might be future therapeutic targets in IBD.
Cystathionine beta-synthase (CBS) is a crucial regulator of plasma levels of the thrombogenic amino acid homocysteine (Hcy). Homocystinuria due to CBS deficiency confers a dramatically increased risk of thrombosis. Early diagnosis usually occurs after the observation of ectopia lentis, mental retardation, or characteristic skeletal abnormalities. Homocystinurics with this phenotype typically carry mutations in the catalytic region of the protein that abolish CBS activity. We describe a novel class of missense mutations consisting of I435T, P422L, and S466L that are located in the non-catalytic C-terminal region of CBS that yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients suffering premature thrombosis and homocystinuric levels of Hcy but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. The P422L and S466L mutants demonstrated a level of CBS activity comparable to that of the AdoMet stimulated wild-type CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the I435T, P422L, and S466L mutants are indistinguishable from wild-type CBS. Our findings illustrate the importance of AdoMet for the regulation of Hcy metabolism and are consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated Hcy.
Nielsen OH, Rudiger N, Gaustadnes M, Horn T. Intestinal interleukin-8 concentration and gene expression in inflammatory bowel disease. Scand J Gastroenterol 1997;32: 1028-1034.Buckground: is an important cytokine for recruitment and activation of polymorphonuclear neutrophils (PMNs), cells that are abundant in the intestinal lesions of ulcerative colitis (UC) and Crohn's disease (CD). The present investigation was conducted to evaluate intestinal IL-8 concentration and IL-8 gene expression in parallel i n inflammatory bowel disease (IBD) patients and a non-inflammatory control group. Methods: The intestinal concentration of IL-8 was measured with a sandwich enzymelinked immunosorbent assay (ELISA) technique (detection limit, 17.4 pg/mg protein), and relative quantitation of IL-8 mRNA transcript levels was done with a reverse transcription polymerase chain reaction (RT-PCR)-based method. Biopsy specimens from 66 humans who underwent colonoscopy-28 with UC, 18 with CD and colonic involvement, and 20 non-inflammatory disease-specific controls who subsequently were found to fulfill the diagnostic criteria for irritable bowel syndrome (1BS)-were included. None had received glucocorticoids within 3 months. Results: Using a one-tailed variance analysis, a significant concordance between increasing IL-8 protein concentrations and disease activity was found both in UC and CD ( P < 0.001). and only trace amounts were detected in IBS biopsy specimens. No differences were found between the two groups of UC and CD patients ( P > 0.05). and no differences were found between quiescent IBD and IBS ( P > 0.05). However, the PCR method showed IL-8 mRNA in 8 of 18 CD patients (44.4%; 95% confidence limits, 21.549.2%) and 7 of 28 UC patients (25.9%; 95% confidence limits, I1.146.3%), as compared with 0 of 20 IBS ( P < 0.005). Increased IL-8 mRNA levels were found only in active CD, which was not the case in UC. No correlation was found between intestinal IL-8 ELISA and IL-8-mRNA levels ( r = 0.24, P > 0.05). Conclusions: The observed correlation between disease activity and expression of the IL-8 gene in active CD colitis but not in UC and the increased IL-8 protein concentrations in affected intestinal segments of IBD as compared with the noninflamed IBS indicate a possible transient IL-8 gene expression or altered mRNA stability in UC and CD, as is well known for other cytokines, such as IL-2. If so, it may form the basis of new therapeutic regimens for IBD like IL-10. The aim of this paper was to assess the IL-8 levels and the expression of the corresponding genes in parallel locally in the inflamed intestine of patients with UC and C D with or Scand
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