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)-gamma 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.
authors.affiliation: Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Krutzik
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ochoa
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Yolanda W
authors.initials: YW
authors.lastname: Ng
authors.forename: Annaliza
authors.initials: A
authors.lastname: Legaspi
authors.forename: Philip T
authors.initials: PT
authors.lastname: Liu
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Godowski
authors.forename: Yumi
authors.initials: Y
authors.lastname: Maeda
authors.forename: Euzenir N
authors.initials: EN
authors.lastname: Sarno
authors.forename: Michael V
authors.initials: MV
authors.lastname: Norgard
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Brennan
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D000818:Animals; D016207:Cytokines / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D007918:Leprosy / Q000276:immunology*; D008074:Lipoproteins / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D011956:Receptors, Cell Surface / Q000032:analysis / Q000502:physiology*; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors
chemical_list: D016207:Cytokines; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors