Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis.
ABSTRACT Tuberculosis, one of the leading causes of death worldwide, stimulates inflammatory responses with beneficial and pathologic consequences. The regulation and nature of an optimal inflammatory response to Mycobacterium tuberculosis remains poorly understood in humans. Insight into mechanisms of negative regulation of the TLR-mediated innate immune response to M. tuberculosis could provide significant breakthroughs in the design of new vaccines and drugs. We hypothesized that TOLLIP and its common variants negatively regulate TLR signaling in human monocytes and are associated with susceptibility to tuberculosis. Using short hairpin RNA knockdown of TOLLIP in peripheral blood human monocytes, we found that TOLLIP suppresses TNF and IL-6 production after stimulation with TLR2 and TLR4 ligands. In contrast, secretion of the anti-inflammatory cytokine IL-10 was induced by TOLLIP. We also discovered two common polymorphisms that are associated with either decreased levels of mRNA expression (rs3750920) or increased IL-6 production (rs5743899) in a sample of 56 healthy volunteers. Furthermore, in a case-population study in Vietnam with 760 cord blood samples and 671 TB case patients, we found that SNPs rs3750920 and rs5743899 were associated with susceptibility to tuberculosis (p = 7.03 × 10(-16) and 6.97 × 10(-7), respectively). These data demonstrate that TOLLIP has an anti-inflammatory effect on TLR signaling in humans and that TOLLIP deficiency is associated with an increased risk of tuberculosis. To our knowledge, these data also show the first associations of TOLLIP polymorphisms with any infectious disease. These data also implicate an unexpected mechanism of negative regulation of TLR signaling in human tuberculosis pathogenesis.
Article: Assessment of the interleukin 1 gene cluster and other candidate gene polymorphisms in host susceptibility to tuberculosis.[show abstract] [hide abstract]
ABSTRACT: A study of tuberculosis cases and healthy blood donor controls from the Western Region of The Gambia, West Africa. To investigate the potential role of candidate gene polymorphisms in host susceptibility to tuberculosis. Single base change polymorphisms in interleukin 1 beta (IL1 beta), interleukin 10 (IL10) and fucosyltransferase-2 (FUT-2), microsatellite polymorphisms in interleukin 1 alpha (IL1 alpha) and IL10 and a minisatellite polymorphism in interleukin 1 receptor antagonist (IL1RA) were typed in over 400 tuberculosis cases and 400 healthy blood donor controls. IL1 gene cluster polymorphisms (IL1RA and possibly IL1 alpha) showed marginally significant association with tuberculosis. In particular IL1RA allele 2 heterozygotes were less frequent among tuberculosis cases than controls (P = 0.03). IL1 beta, IL10 and FUT-2 polymorphisms were not associated with tuberculosis. Genetic susceptibility to tuberculosis among Gambians may be partly determined by genes in the IL1 gene cluster on chromosome 2. Further association studies will be required on other population groups to confirm whether these results are of biological significance.Tubercle and Lung Disease 02/1998; 79(2):83-9.
Article: The toll-like receptor 4 Asp299Gly variant and tuberculosis susceptibility in HIV-infected patients in Tanzania.[show abstract] [hide abstract]
ABSTRACT: Toll-like receptor 4 (TLR4) plays an important role in the pattern recognition of Mycobacterium tuberculosis, and polymorphisms in the TLR4 gene influence the function of the receptor. We therefore investigated in a cohort of HIV-infected Tanzanian patients whether the Asp299Gly TLR4 polymorphism is associated with the development of active tuberculosis. We found a greater risk of developing active tuberculosis as well as a reduction in CD4 T-cell counts in patients with the Asp299Gly TLR4 polymorphism.AIDS 07/2007; 21(10):1375-7. · 6.24 Impact Factor