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Human TOLLIP Regulates TLR2 and TLR4 Signaling and Its Polymorphisms Are Associated with Susceptibility to Tuberculosis

Javeed A. Shah, Jay C. Vary, Tran T. H. Chau, Nguyen D. Bang, Nguyen T. B. Yen, Jeremy J. Farrar, Sarah J. Dunstan and Thomas R. Hawn
J Immunol August 15, 2012, 189 (4) 1737-1746; DOI: https://doi.org/10.4049/jimmunol.1103541
Javeed A. Shah
*Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195;
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Jay C. Vary
†Division of Dermatology, University of Washington, Seattle, WA 98195;
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Tran T. H. Chau
‡Centre for Tropical Medicine, Oxford University Clinical Research Unit, Ho Chi Minh City, District 5, Vietnam;
§Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford OX3 7LJ, United Kingdom; and
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Nguyen D. Bang
¶Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases, Ho Chi Minh City, Vietnam
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Nguyen T. B. Yen
¶Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases, Ho Chi Minh City, Vietnam
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Jeremy J. Farrar
‡Centre for Tropical Medicine, Oxford University Clinical Research Unit, Ho Chi Minh City, District 5, Vietnam;
§Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford OX3 7LJ, United Kingdom; and
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Sarah J. Dunstan
‡Centre for Tropical Medicine, Oxford University Clinical Research Unit, Ho Chi Minh City, District 5, Vietnam;
§Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, Oxford University, Oxford OX3 7LJ, United Kingdom; and
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Thomas R. Hawn
*Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA 98195;
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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.

Footnotes

  • This work was supported by National Institute of Allergy and Infectious Diseases at the National Institutes of Health Grants 1K24AI089794 (to T.R.H.) and 5T32AI00704432 (to J.A.S.), the Burroughs Wellcome Foundation (to T.R.H.), and the Wellcome Trust of Great Britain (to J.J.F.).

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    HTD
    Hospital for Tropical Diseases
    OR
    odds ratio
    PNT
    Pham Ngoc Thach
    PTB
    pulmonary tuberculosis
    shRNA
    short hairpin RNA
    SNP
    single nucleotide polymorphism
    TB
    tuberculosis
    TBM
    tuberculous meningitis.

  • Received December 8, 2011.
  • Accepted June 4, 2012.
  • Copyright © 2012 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 189 (4)
The Journal of Immunology
Vol. 189, Issue 4
15 Aug 2012
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Human TOLLIP Regulates TLR2 and TLR4 Signaling and Its Polymorphisms Are Associated with Susceptibility to Tuberculosis
Javeed A. Shah, Jay C. Vary, Tran T. H. Chau, Nguyen D. Bang, Nguyen T. B. Yen, Jeremy J. Farrar, Sarah J. Dunstan, Thomas R. Hawn
The Journal of Immunology August 15, 2012, 189 (4) 1737-1746; DOI: 10.4049/jimmunol.1103541

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Human TOLLIP Regulates TLR2 and TLR4 Signaling and Its Polymorphisms Are Associated with Susceptibility to Tuberculosis
Javeed A. Shah, Jay C. Vary, Tran T. H. Chau, Nguyen D. Bang, Nguyen T. B. Yen, Jeremy J. Farrar, Sarah J. Dunstan, Thomas R. Hawn
The Journal of Immunology August 15, 2012, 189 (4) 1737-1746; DOI: 10.4049/jimmunol.1103541
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