Activation and regulation of Toll-like receptors 2 and 1 in human leprosy.
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.
Krutzik
Stephan R
SR
Division of Dermatology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
Ochoa
Maria Teresa
MT
Sieling
Peter A
PA
Uematsu
Satoshi
S
Ng
Yolanda W
YW
Legaspi
Annaliza
A
Liu
Philip T
PT
Cole
Stewart T
ST
Godowski
Paul J
PJ
Maeda
Yumi
Y
Sarno
Euzenir N
EN
Norgard
Michael V
MV
Brennan
Patrick J
PJ
Akira
Shizuo
S
Rea
Thomas H
TH
Modlin
Robert L
RL
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
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