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

Research output: Contribution to journalArticle

255 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 languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalNature medicine
Volume9
Issue number5
DOIs
StatePublished - May 1 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Krutzik, S. R., Ochoa, M. T., Sieling, P. A., Uematsu, S., Ng, Y. W., Legaspi, A., Liu, P. T., Cole, S. T., Godowski, P. J., Maeda, Y., Sarno, E. N., Norgard, M. V., Brennan, P. J., Akira, S., Rea, T. H., & Modlin, R. L. (2003). Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nature medicine, 9(5), 525-532. https://doi.org/10.1038/nm864