Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

Stephan R. Krutzik; Maria Teresa Ochoa; Peter A. Sieling; Satoshi Uematsu; Yolanda W. Ng; Annaliza Legaspi; Philip T. Liu; Stewart T. Cole; Paul J. Godowski; Yumi Maeda; Euzenir N. Sarno; Michael V. Norgard; Patrick J. Brennan; Shizuo Akira; Thomas H. Rea; Robert L. Modlin

doi:10.1038/nm864

Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

Stephan R. Krutzik, Maria Teresa Ochoa, Peter A. Sieling, Satoshi Uematsu, Yolanda W. Ng, Annaliza Legaspi, Philip T. Liu, Stewart T. Cole, Paul J. Godowski, Yumi Maeda, Euzenir N. Sarno, Michael V. Norgard, Patrick J. Brennan, Shizuo Akira, Thomas H. Rea, Robert L. Modlin

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280 Scopus citations

Abstract

The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.

Original language	English (US)
Pages (from-to)	525-532
Number of pages	8
Journal	Nature medicine
Volume	9
Issue number	5
DOIs	https://doi.org/10.1038/nm864
State	Published - May 1 2003

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm864

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@article{523b9cd37a6648208c12a4b1f05f442c,

title = "Activation and regulation of Toll-like receptors 2 and 1 in human leprosy",

abstract = "The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.",

author = "Krutzik, {Stephan R.} and Ochoa, {Maria Teresa} and Sieling, {Peter A.} and Satoshi Uematsu and Ng, {Yolanda W.} and Annaliza Legaspi and Liu, {Philip T.} and Cole, {Stewart T.} and Godowski, {Paul J.} and Yumi Maeda and Sarno, {Euzenir N.} and Norgard, {Michael V.} and Brennan, {Patrick J.} and Shizuo Akira and Rea, {Thomas H.} and Modlin, {Robert L.}",

note = "Funding Information: Acknowledgments We thank D. Williams and T. Gillis (National Hansen{\textquoteright}s Disease Programs) for use of their unpublished data on expression of ML1966 mRNA, W. Chung for technical assistance and S. Smale for critical comments on the manuscript and scientific discussion. This work was supported in part by grants from the National Institutes of Health (AI07126, AI22553 and AI47866) and the World Health Organization (IMMLEP).",

year = "2003",

month = may,

day = "1",

doi = "10.1038/nm864",

language = "English (US)",

volume = "9",

pages = "525--532",

journal = "Nature medicine",

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T1 - Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

AU - Krutzik, Stephan R.

AU - Ochoa, Maria Teresa

AU - Sieling, Peter A.

AU - Uematsu, Satoshi

AU - Ng, Yolanda W.

AU - Legaspi, Annaliza

AU - Liu, Philip T.

AU - Cole, Stewart T.

AU - Godowski, Paul J.

AU - Maeda, Yumi

AU - Sarno, Euzenir N.

AU - Norgard, Michael V.

AU - Brennan, Patrick J.

AU - Akira, Shizuo

AU - Rea, Thomas H.

AU - Modlin, Robert L.

N1 - Funding Information: Acknowledgments We thank D. Williams and T. Gillis (National Hansen’s Disease Programs) for use of their unpublished data on expression of ML1966 mRNA, W. Chung for technical assistance and S. Smale for critical comments on the manuscript and scientific discussion. This work was supported in part by grants from the National Institutes of Health (AI07126, AI22553 and AI47866) and the World Health Organization (IMMLEP).

PY - 2003/5/1

Y1 - 2003/5/1

N2 - The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.

AB - The expression and activation of Toll-like receptors (TLRs) was investigated in leprosy, a spectral disease in which clinical manifestations correlate with the type of immune response mounted toward Mycobacterium leprae. TLR2-TLR1 heterodimers mediated cell activation by killed M. leprae, indicating the presence of triacylated lipoproteins. A genome-wide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19-kD and 33-kD lipoproteins activated both monocytes and dendritic cells. Activation was enhanced by type-1 cytokines and inhibited by type-2 cytokines. In addition, interferon (IFN)-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced TLR1 expression in monocytes and dendritic cells, respectively, whereas IL-4 downregulated TLR2 expression. TLR2 and TLR1 were more strongly expressed in lesions from the localized tuberculoid form (T-lep) as compared with the disseminated lepromatous form (L-lep) of the disease. These data provide evidence that regulated expression and activation of TLRs at the site of disease contribute to the host defense against microbial pathogens.

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DO - 10.1038/nm864

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JO - Nature medicine

JF - Nature medicine

IS - 5

ER -

Activation and regulation of Toll-like receptors 2 and 1 in human leprosy

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