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Title: An investigation of the role of interleukin-6 in systemic-onset juvenile chronic arthritis
Author: Fishman, Daniel
ISNI:       0000 0001 3467 700X
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1999
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Serum IL-6 levels in the acute phase of systemic-onset juvenile chronic arthritis (S-JCA) are markedly elevated, with additional peaks and troughs that exactly parallel the rise and fall of the fever characteristic of this condition. One explanation for this unique feature is that the control of expression of IL-6 in S-JCA patients is different to that in normal people. This thesis discusses research conducted to examine the hypothesis that this is due to polymorphisms in the region of the IL-6 gene controlling its expression. Single-strand conformational polymorphism analysis of a PCR-generated fragment from the 5' flanking region of the IL-6 gene (-550 to +61) indicated the existence of polymorphisms. Sequencing of this region from 57 individuals revealed two novel polymorphisms; a G/C polymorphism at position -174; and a variation in the number of A and T bases in an AnTn tract between positions -392 and -373. RFLP analysis of the -174 polymorphism in 59 Caucasian S-JCA patients demonstrated that they had a lower C allele frequency than a group of healthy Caucasians (n=72) (0.35 vs 0.53). The overall genotype distribution between the groups was significantly different (x2=4.15, p=0.0002). Moreover, the patients had a significantly lower CC genotype frequency (0.033 vs 0.32, p<0.0001). Luciferase reporter constructs containing either allele were transiently transfected into HeLa cells. The C(A8T12) construct showed a 0.624 ±0.15 fold lower (p<0.005) basal expression of luciferase, compared to the G(A8T12) construct. Following stimulation with lipopolysaccharide or interleukin-1, luciferase expression from the C(A8T12) construct did not change. However, luciferase expression from the G(A8T12) construct increased by 2.35 ± 0.10 fold and 3.60 ± 0.26 fold, respectively (both p<0.001). Deletion of the sequence upstream of the AP-1 site (at -283 ~ -277) resulted in loss of this differential response and an overall reduction in expression. These results suggest that there is a genetically determined difference in the degree of the IL-6 response to stressful stimuli between individuals, and that the CC genotype may be protective against the development of S-JCA.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Genetics