Interleukin-10 (IL-10) gene polymorphism as a potential host susceptibility factor in tuberculosis
Introduction
Tuberculosis (TB) remains to be a leading cause of morbidity and mortality in developing countries. However, the incidence of disease increases in developed countries [1]. One third of the world’s population is infected by Mycobacterium tuberculosis but only about 5% of the infected people develop disease within the first year of infection (primary TB) and other 5% develop the disease later in life (reactivation TB). At present it is impossible to predict in whom the disease will develop and progress through several stages from mild to severe. There are several reports demonstrating that host genetic factors play significant roles in susceptibility to TB [2]. Therefore, the identification of host genes responsible for susceptibility and resistance to TB should provide a significant contribution for understanding of the pathogenesis and may lead to the development of new prophylaxis and treatment strategies.
Cytokines produced at the site of disease after interactions between T lymphocytes and infected macrophages are essential for the pathogenesis of TB [3]. The course of M. tuberculosis infection is regulated by two distinct T cell cytokine patterns. T helper 1 (Th1) cytokines, IL-2 and IFN-γ, are associated with resistance to infection, whereas Th2 cytokines, IL-4 and IL-13, are associated with progressive disease [4]. In addition, IL-10, one of the T regulatory cytokines, seem to play a pivotal role during the chronic/latent stage of pulmonary TB, with increased production playing a potentially central role in promoting reactivation of TB [5]. Another T regulatory cytokine TGF-β, mainly produced by Th3 cells, may be beneficial or detrimental by inducing fibrosis or by contributing cavity formation, respectively, [6]. Of fundamental immunologic importance are the factors, that influence the nature of cytokine response, such as polymorphisms of cytokine genes. Polymorphisms in several cytokine genes have been described and demonstrated to influence gene transcription, leading to interindividual variations in cytokine production [7], [8]. Cytokine gene polymorphisms have been shown to be involved in the susceptibility, severity and clinical outcome of several diseases including infectious ones [7], [8], [9], [10].
The aim of this work was to determine whether there is any association between cytokine gene polymorphisms and susceptibility to TB. We performed a study in Turkish patients affected with different clinical forms of TB and healthy control subjects to determine the influence of single nucleotide polymorphisms in five cytokines (IL-6, IL-10, IFN-γ, TGF-β and TNF-α) on susceptibility and disease expression.
Section snippets
Patients and controls
Blood samples, collected in ethylenediamine tetraacetate sterile tubes, were obtained from 81 Turkish patients affected by different forms of TB (Table 1). TB was diagnosed on the basis of radiographic and clinical presentation, positive special staining and cultures for M. tuberculosis and, in some cases, the finding of caseating granulomas in biopsies. A control group was composed of 50 healthy organ donors, matched for age and sex, ethnicity and from the same geographical area as the
Results
We evaluated the frequencies of cytokine gene polymorphisms in patients affected by different clinical forms of TB (Table 1) and in healthy volunteers.
The frequency of IL-10 (−1082, −819, −592) GCC/ACC genotype was significantly higher in TB patients when compared with those of healthy controls (37.0% vs 20.0%, p: 0.04), whereas significantly lower frequencies of IL-10 ACC/ATA genotype was observed in the patient group (14.8% vs 32.0%, p: 0.02). Statistical significant differences for both
Discussion
Single nucleotide polymorphisms in several candidate genes have been linked to relatively increased risk for TB [9]. In this polymorphism-association study, we investigated the significance of the relationship between several cytokine gene polymorphisms and susceptibility to TB.
Interleukin-10 is a multifunctional cytokine first described as cytokine synthesis inhibitory factor, which inhibits IFN-γ cytokine production by Th1 cells in mice [11], [12]. It inhibits monocyte/macrophage function
Acknowledgment
This study was supported by the grant from Uludag University, Bursa, Turkey (Grant number 2002/35).
References (41)
- et al.
The return of tuberculosis
Diagn Microbiol Infect Dis
(1999) The immunopathogenesis of tuberculosis: a new working hypothesis
Trends Microbiol
(1998)- et al.
Hijacking and exploitation of IL-10 by intracellular pathogens
Trends Microbiol
(2001) - et al.
IL-10 and TNF-alpha polymorphisms in a sample of Sicilian patients affected by tuberculosis: implication for ageing and life span expectancy
Mech Ageing Dev
(2003) - et al.
Cytokine gene polymorphisms in Colombian patients with different clinical presentations of tuberculosis
Tuberculosis
(2006) - et al.
Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis
Tuber Lung Dis
(1998) - et al.
A single nucleotide polymorphism in the first intron of the human IFN-gamma gene: absolute correlation with a polymorphic CA microsatellite marker of high IFN-gamma production
Hum Immunol
(2000) - et al.
Evidence that genetic susceptibility to Mycobacterium tuberculosis in a Brazilian population is under oligogenic control: linkage study of the candidate genes NRAMP1 and TNFA
Tuber Lung Dis
(1997) - et al.
Inflammatory and immunomodulatory roles of TGF-beta
Immunol Today
(1989) The genomics and genetics of human infectious disease susceptibility
Annu Rev Genomics Hum Genet
(2001)
Regulation of immunity to parasites by T cells and T cell-derived cytokines
Annu Rev Immunol
Cytokines and tuberculosis
J Leukoc Biol
In vivo IL-10 production reactivates chronic pulmonary tuberculosis in C57BL/6 mice
J Immunol
Cytokine gene polymorphism in human disease: on-line databases
Genes Immun
Cytokine gene polymorphism in human disease: on-line databases, supplement 1
Genes Immun
The immunogenetics of human infectious diseases
Annu Rev Immunol
Cytokine gene polymorphism in human disease: on-line databases, supplement 2
Genes Immun
Identification of functional domains on human interleukin 10
Proc Natl Acad Sci USA
Interleukin-10 and the interleukin-10 receptor
Annu Rev Immunol
Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes
J Exp Med
Cited by (90)
Association of TNF-α IL-10 and IL-6 promoter polymorphisms in pulmonary tuberculosis patients and their household contacts of younger age group
2018, Comparative Immunology, Microbiology and Infectious DiseasesEvaluation of TNF-alpha gene (G308A) and MBL2 gene codon 54 polymorphisms in Turkish patients with tuberculosis
2017, Journal of Infection and Public Health