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Cited by 295Tuberculosis Research and EpidemiologyGenetic Associations and EpidemiologyImmune Response and Inflammation

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

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Wilkinson, Robert J., Patel, Punita, Llewelyn, Martin, Hirsch, Christina S., Pasvol, Geoffrey, Snounou, Georges, Davidson, Robert N., Toossi, Zahra·1999·The Journal of Experimental Medicine
DOI 10.1084/jem.189.12.1863PMC PMC2192963
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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.

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Crossref · 10.1084/jem.189.12.1863

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Figure 1 Association between IL-1Ra genotype and the monocyte production of IL-1Ra in response to M. tuberculosis and PPD. The amount of IL-1Ra produced by PBMCs from healthy, PPD-nonreactive donors during a 10-h coculture with either M. tuberculosis (A) or PPD (B) was determined by ELISA. Values were normalized to the number of monocytes present in the culture. The response of IL-1Ra A2+ individuals was higher at all doses of either stimuli.
Figure 1 Association between IL-1Ra genotype and the monocyte production of IL-1Ra in response to M. tuberculosis and PPD. The amount of IL-1Ra produced by PBMCs from healthy, PPD-nonreactive donors during a 10-h coculture with either M. tuberculosis (A) or PPD (B) was determined by ELISA. Values were normalized to the number of monocytes present in the culture. The response of IL-1Ra A2+ individuals was higher at all doses of either stimuli.CC BY-NC-SA · PubMed Central
Figure 2 Relationship between polymorphism in IL-1Ra and the IL-1Ra/IL-1β ratio. The IL-1β content of the supernates shown in Fig. 1 was also assayed by ELISA. The molar ratio of IL-1Ra/IL-1β was calculated. This ratio is selectively increased in IL-1Ra A2+ individuals in response to PPD and M. tuberculosis, accentuated by the finding that IL-1Ra A2+ subjects tended to produce less IL-1β in response to M. tuberculosis. By comparison, the ratio in response to LPS was not different between IL-1Ra A2+ and A2− subjects. Response to PPD is data from eight individuals.
Figure 2 Relationship between polymorphism in IL-1Ra and the IL-1Ra/IL-1β ratio. The IL-1β content of the supernates shown in Fig. 1 was also assayed by ELISA. The molar ratio of IL-1Ra/IL-1β was calculated. This ratio is selectively increased in IL-1Ra A2+ individuals in response to PPD and M. tuberculosis, accentuated by the finding that IL-1Ra A2+ subjects tended to produce less IL-1β in response to M. tuberculosis. By comparison, the ratio in response to LPS was not different between IL-1Ra A2+ and A2− subjects. Response to PPD is data from eight individuals.CC BY-NC-SA · PubMed Central
Figure 3 (A) Effect of IL-6 and IL-10 on the IL-1Ra/IL-1β ratio. PBMCs were cultured with M. tuberculosis in the presence or absence of rhIL-6 or rhIL-10 over a dose range of 0.1–10 ng/ml. Culture supernates were assayed for IL-1Ra and IL-1β and the molar ratio calculated. IL-10 increased the ratio significantly even at the lowest dose (P < 0.02), whereas rhIL-6 had no significant effect. (B) Effect of IFN-γ and IL-4 on the IL-1Ra/IL-1β ratio. PBMCs were cultured with M. tuberculosis in the presence or absence of rhIFN-γ or rhIL-4 over a dose range of 0.1–10 ng/ml. Culture supernates were assayed for IL-1Ra and IL-1β and the molar ratio calculated. IL-4 increased the ratio markedly even at the lowest dose (P < 0.01), whereas higher doses of IFN-γ were required to cause a significant reduction.
Figure 3 (A) Effect of IL-6 and IL-10 on the IL-1Ra/IL-1β ratio. PBMCs were cultured with M. tuberculosis in the presence or absence of rhIL-6 or rhIL-10 over a dose range of 0.1–10 ng/ml. Culture supernates were assayed for IL-1Ra and IL-1β and the molar ratio calculated. IL-10 increased the ratio significantly even at the lowest dose (P < 0.02), whereas rhIL-6 had no significant effect. (B) Effect of IFN-γ and IL-4 on the IL-1Ra/IL-1β ratio. PBMCs were cultured with M. tuberculosis in the presence or absence of rhIFN-γ or rhIL-4 over a dose range of 0.1–10 ng/ml. Culture supernates were assayed for IL-1Ra and IL-1β and the molar ratio calculated. IL-4 increased the ratio markedly even at the lowest dose (P < 0.01), whereas higher doses of IFN-γ were required to cause a significant reduction.CC BY-NC-SA · PubMed Central
Figure 4 Association between IL-1Ra haplotype and the cutaneous response to PPD of M. tuberculosis. The mean diameter of induration in response to one tuberculin unit of PPD in tuberculosis patients of various genotypes is shown. The proportion of IL-1Ra A2+ was highest (60%) in patients with an absent response and lowest in the category 21–30 mm (25%), falling gradually to its overall frequency (41%) as successively higher grades of Mantoux were considered.
Figure 4 Association between IL-1Ra haplotype and the cutaneous response to PPD of M. tuberculosis. The mean diameter of induration in response to one tuberculin unit of PPD in tuberculosis patients of various genotypes is shown. The proportion of IL-1Ra A2+ was highest (60%) in patients with an absent response and lowest in the category 21–30 mm (25%), falling gradually to its overall frequency (41%) as successively higher grades of Mantoux were considered.CC BY-NC-SA · PubMed Central

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Metadata

Authors
Wilkinson, R. J., Patel, P., Llewelyn, M., Hirsch, C. S., Pasvol, G., Snounou, G., Davidson, R. N., & Toossi, Z.
Affiliations
Northwick Park Hospital (GB)
Corresponding author
Toossi, Zahra
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1999-06-21
Volume
189
Issue
12
Pages
1863-1874
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.189.12.1863
PMC
PMC2192963
OpenAlex
W2156995597
Cited by
295
References
58
Citations by year
2026: 1 · 2025: 1 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 8 · 2019: 4 · 2018: 9 · 2017: 7 · 2016: 6 · 2015: 11 · 2014: 9 · 2013: 10 · 2012: 9
FWCI
14.57
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Spiral (Imperial College London) (submittedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion)
Funders
  • Wellcome Trust
  • Imperial College London
  • National Institutes of Health
  • Medical Research Council
  • National Institute of Allergy and Infectious Diseases (AI-18471)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
interleukin-1 receptor antagonist, IL-1β, genetic polymorphism, host genetic susceptibility, Mycobacterium tuberculosis, pleural tuberculosis, tuberculin skin test
MeSH terms
Cell Division, Genotype, Haplotypes, Humans, Hypersensitivity, Delayed, Interleukin-1, Leukocytes, Mycobacterium tuberculosis, Polymorphism, Genetic, RNA, Messenger, Sialoglycoproteins, Tuberculin, Tuberculosis, Interleukin-4, Interleukin-6, Interleukin-10, Receptors, Interleukin-1, Interleukin 1 Receptor Antagonist Protein

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