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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1860-1868
PHAGOCYTES
Role of Toll-like receptor 2 (TLR2) in neutrophil activation:
GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils
Evelyn A. Kurt-Jones,
Leisa Mandell,
Constance Whitney,
Alison Padgett,
Kerri Gosselin,
Peter E. Newburger, and
Robert W. Finberg
From the Departments of Medicine and
Pediatrics, University of Massachusetts Medical School, Worcester, MA.
In vitro studies as well as clinical trials indicate that the
cytokines granulocyte-macrophage colony-stimulating factor
(GM-CSF) and granulocyte colony-stimulating factor (G-CSF) enhance the ability of neutrophils (polymorphonuclear leukocytes) to eliminate microbial organisms. Toll-like receptor (TLR) proteins,
homologs of the Drosophila protein Toll, have been found on the
surface of mammalian cells and are important in the responses of
macrophages to bacterial, viral, and fungal antigens. TLR4 is critical
for the response to lipopolysaccharide (LPS) of gram-negative bacteria, while TLR2 is important for response to gram-positive bacteria, bacterial peptides, and yeast zymosan. We demonstrate that TLR2, but
very little TLR4, is present on the surface of human neutrophils. In
addition we demonstrate that GM-CSF and G-CSF dramatically up-regulate
TLR2 and CD14 surface expression. GM-CSF treatment also up-regulates
TLR2 and CD14 mRNA levels in neutrophils. In addition to increasing
receptor expression, GM-CSF treatment enhanced the interleukin 8 (IL-8)
secretion and superoxide priming responses of neutrophils to
stimulation with TLR2 ligands, including zymosan, peptidoglycan, and
lipoarabinomannan. The human monocyte response to crude bacterial LPS
is composed of a TLR4-specific response to the pure LPS component and a
TLR2-dependent response to associated lipopeptides. The removal of TLR2
lipopeptide components from LPS by phenol re-extraction substantially
reduced both the IL-8 and superoxide response of the stimulated
neutrophils, indicating that, unlike monocytes, the neutrophil response
is preferentially directed to TLR2 ligands. Thus, our studies
demonstrate that GM-CSF dramatically enhances the functional response
of neutrophils to TLR2 ligands, including LPS-associated lipopeptides.
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