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Blood, Vol. 93 No. 7 (April 1), 1999:
pp. 2173-2185
Metalloproteinases Are Involved in Lipopolysaccharide- and Tumor
Necrosis Factor- -Mediated Regulation of CXCR1 and CXCR2
Chemokine Receptor Expression
Masud H. Khandaker,
Gordon Mitchell,
Luoling Xu,
Joseph D. Andrews,
Rajkumari Singh,
Harry Leung,
Joaquín Madrenas,
Stephen S.G. Ferguson,
Ross D. Feldman, and
David J. Kelvin
From the Departments of Microbiology and Immunology, Medicine,
Pharmacology and Toxicology, and Zoology, The University of Western
Ontario and the London Health Sciences Centre, London; and the
Laboratory of Molecular Immunology and Inflammation, John P. Robarts
Research Institute, London, Ontario, Canada.
The neutrophil-specific G-protein-coupled chemokine receptors,
CXCR1 and CXCR2, bind with high affinity to the potent chemoattractant interleukin-8 (IL-8). The mechanisms of IL-8 receptor regulation are
not well defined, although previous studies have suggested a process of
ligand-promoted internalization as a putative regulatory pathway.
Herein, we provide evidence for two distinct processes of CXCR1 and
CXCR2 regulation. Confocal microscopy data showed a redistribution of
CXCR1 expression from the cell surface of neutrophils to internal
compartments after stimulation with IL-8, whereas stimulation with
bacterial lipopolysaccharide (LPS) or tumor necrosis factor-
(TNF-) did not induce CXCR1 internalization but instead mediated a
significant loss of membrane-proximal CXCR1 staining intensity. To
investigate whether proteolytic cleavage was the mechanism responsible
for LPS- and TNF--induced downmodulation of IL-8 receptors, we
tested a panel of proteinase inhibitors. The downmodulation of CXCR1
and CXCR2 by LPS and TNF- was most dramatically inhibited by
metalloproteinase inhibitors; 1,10-phenanthroline and EDTA
significantly attenuated LPS- and TNF--induced loss of CXCR1 and
CXCR2 cell surface expression. Metalloproteinase inhibitors also
blocked the release of CXCR1 cleavage fragments into the cell
supernatants of LPS- and TNF--stimulated neutrophils. In addition,
while treatment of neutrophils with LPS and TNF- inhibited IL-8
receptor-mediated calcium mobilization and IL-8-directed neutrophil
chemotaxis, both 1,10-phenanthroline and EDTA blocked these inhibitory
processes. In contrast, metalloproteinase inhibitors did not affect
IL-8-mediated downmodulation of CXCR1 and CXCR2 cell surface
expression or receptor signaling. Thus, these findings may provide
further insight into the mechanisms of leukocyte regulation during
immunologic and inflammatory responses.
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