Influence of Polymorphism in the Genes for the Interleukin (IL)-1 Receptor Antagonist and IL-1β on Tuberculosis

Abstract

Several lines of evidence suggest that host genetic factors controlling the immune response influence infection by Mycobacterium tuberculosis. The proinflammatory cytokine interleukin (IL)-1β and its antagonist, IL-1Ra (IL-1 receptor agonist), are strongly induced by M. tuberculosis and are encoded by polymorphic genes. The induction of both IL-1Ra mRNA and secreted protein by M. tuberculosis in IL-1Ra allele A2–positive (IL-1Ra A2+) healthy subjects was 1.9-fold higher than in IL-1Ra A2− subjects. The M. tuberculosis–induced expression of mRNA for IL-1β was higher in subjects of the IL-1β (+3953) A1+ haplotype (P = 0.04). The molar ratio of IL-1Ra/IL-1β induced by M. tuberculosis was markedly higher in IL-1Ra A2+ individuals (P < 0.05), with minor overlap between the groups, reflecting linkage between the IL-1Ra A2 and IL-1β (+3953) A2 alleles. In M. tuberculosis–stimulated peripheral blood mononuclear cells, the addition of IL-4 increased IL-1Ra secretion, whereas interferon γ increased and IL-10 decreased IL-1β production, indicative of a differential influence on the IL-1Ra/IL-1β ratio by cytokines. In a study of 114 healthy purified protein derivative–reactive subjects and 89 patients with tuberculosis, the frequency of allelic variants at two positions (−511 and +3953) in the IL-1β and IL-1Ra genes did not differ between the groups. However, the proinflammatory IL-1Ra A2−/IL-1β (+3953) A1+ haplotype was unevenly distributed, being more common in patients with tuberculous pleurisy (92%) in comparison with healthy M. tuberculosis–sensitized control subjects or patients with other disease forms (57%, P = 0.028 and 56%, P = 0.024, respectively). Furthermore, the IL-1Ra A2+ haplotype was associated with a reduced Mantoux response to purified protein derivative of M. tuberculosis: 60% of tuberculin-nonreactive patients were of this type. Thus, the polymorphism at the IL-1 locus influences the cytokine response and may be a determinant of delayed-type hypersensitivity and disease expression in human tuberculosis.

Polymorphisms in the interleukin‐1 receptor antagonist and interleukin‐6 genes affect risk of osteolysis in patients with total hip arthroplasty

“…Wilkinson et al found that carriage of this allele resulted in an almost 2-fold increase in IL-1Ra mRNA induction in LPS-stimulated PBMCs compared with PBMCs carrying only the T allele at this site (38), and this is consistent with our study findings. Schrijver et al found an allele dose-response relationship between C allele copy number and IL-1Ra protein production in human whole blood stimulated with LPS (39).…”

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

“…2 In this context, several polymorphisms in genes associated with immune defense against M. tuberculosis have been tested. Polymorphisms in the NRAMP1 [3][4][5][6][7] and the genes for the vitamin D receptor, 8,9 IL-12 receptor b1, 10,11 IL-1, 12,13 IL-10, 13 and TNF-a 14 have been reported to be factors involved in the development of clinical TB. However, these associations have not been robust or generalizable in most cases.…”

T helper 1-type immunity to trophoblast antigens in women with a history of recurrent pregnancy loss is associated with polymorphism of the IL1B promoter region

“…10 Recent studies have shown that polymorphism of these genes influences cytokine production and susceptibility to certain infectious, inflammatory and malignant diseases. [12][13][14] It was also reported that IL1RN polymorphism was associated with recurrent pregnancy loss. 27 In the present study, we investigated polymorphisms of the IL1B gene and Th1 cytokine production in women with RPL.…”

“…A growing body of evidence has 20 September 2001 shown that polymorphism of cytokine genes influences cytokine production and may be associated with susceptibility to certain infectious, inflammatory and autoimmune diseases. [10][11][12][13][14] Cytokines in the IL-1 system (IL-1␣, IL-1␤ and IL-1 receptor antagonist (IL-1Ra)) are produced at the maternal-fetal interface during early pregnancy. 15 The IL-1 system may be involved in the regulation of Th1/Th2 cytokine production, since IL-1 can function as a costimulator for Th2 cell generation in both rodents and humans [16][17][18][19] and may influence IFN-␥ production mediated by natural killer (NK) and T cells.…”

“…25,26,35 Tandem repeat polymorphism in the second intron of IL1RN was analyzed by PCR-gel electrophoresis as described. 13 a Number of alleles. Data were statistically analyzed by Fisher's exact test (two-tailed) with the aid of INSTAT (GraphPad, San Diego, CA, USA).…”