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Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, United Kingdom
The 14-kDa myeloid-related protein (MRP-14) and its heterodimeric
partner, MRP-8, are members of the S100 family of calcium-binding
proteins (S100A9 and S100A8, respectively). Their importance in
neutrophil function is implied by their unusual abundance in neutrophil
cytosol (
40% of cytosolic protein). Previous work from our
laboratory has demonstrated the extracellular association of these
proteins with vascular endothelium adjacent to transmigrating
leukocytes. We report here a function for MRP-14 as a stimulator of
neutrophil adhesion mediated by the ß2 integrin,
Mac-1. MRP-14 is an affinity regulator of Mac-1 because it promotes
binding of soluble ligand and expression of an "activation
reporter" epitope of high affinity ß2 integrins
recognized by mAb24. The activity of MRP-14 is confined to regulating
integrin function because, unlike other inflammatory agonists, there
was no release of L-selectin, up-regulation of cytosolic Mac-1, or
induction of neutrophil respiratory burst or calcium flux. Furthermore,
MRP-14 does not act as a chemoattractant or cause alterations in cell
shape or cytoskeleton. MRP-8 has a regulatory role in MRP-14 activity,
inhibiting the adhesion induced by MRP-14 through the formation of the
heterodimer. In terms of mechanism of action, MRP-14 does not increase
Mac-1 function by direct binding to this integrin but recognizes a
distinct receptor on neutrophils. This receptor interaction is
pertussis toxin sensitive, indicating that MRP-14-generated signals
leading to a Mac-1 affinity increase are heterotrimeric G protein
dependent. We postulate that MRP-14 and MRP-8 are important in vivo
candidates for the regulated adhesion of neutrophils through control of
Mac-1 activity.
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R. K. Kumar, Z. Yang, S. Bilson, S. Thliveris, B. E. Cooke, and C. L. Geczy Dimeric S100A8 in human neutrophils is diminished after phagocytosis J. Leukoc. Biol., July 1, 2001; 70(1): 59 - 64. [Abstract] [Full Text] [PDF]
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H. J. Strausbaugh and S. D. Rosen A Potential Role for Annexin 1 as a Physiologic Mediator of Glucocorticoid-Induced L-Selectin Shedding from Myeloid Cells J. Immunol., May 15, 2001; 166(10): 6294 - 6300. [Abstract] [Full Text] [PDF]
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K. Xu, T. Yen, and C. L. Geczy IL-10 Up-Regulates Macrophage Expression of the S100 Protein S100A8 J. Immunol., May 15, 2001; 166(10): 6358 - 6366. [Abstract] [Full Text] [PDF]
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G. Srikrishna, K. Panneerselvam, V. Westphal, V. Abraham, A. Varki, and H. H. Freeze Two Proteins Modulating Transendothelial Migration of Leukocytes Recognize Novel Carboxylated Glycans on Endothelial Cells J. Immunol., April 1, 2001; 166(7): 4678 - 4688. [Abstract] [Full Text] [PDF]
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I. Eue, B. Pietz, J. Storck, M. Klempt, and C. Sorg Transendothelial migration of 27E10+ human monocytes Int. Immunol., November 1, 2000; 12(11): 1593 - 1604. [Abstract] [Full Text] [PDF]
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K. Xu and C. L. Geczy IFN-{gamma} and TNF Regulate Macrophage Expression of the Chemotactic S100 Protein S100A8 J. Immunol., May 1, 2000; 164(9): 4916 - 4923. [Abstract] [Full Text] [PDF]
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 B. H. Schønning, M. Bévort, S. Mikkelsen, M. Andresen, P. Thomsen, H. Leffers, and B. Norrild Human papillomavirus type 16 E7-regulated genes: regulation of S100P and ADP/ATP carrier protein genes identified by differential-display technology J. Gen. Virol., April 1, 2000; 81(4): 1009 - 1015. [Abstract] [Full Text]
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C. Kerkhoff, M. Klempt, V. Kaever, and C. Sorg The Two Calcium-binding Proteins, S100A8 and S100A9, Are Involved in the Metabolism of Arachidonic acid in Human Neutrophils J. Biol. Chem., November 12, 1999; 274(46): 32672 - 32679. [Abstract] [Full Text] [PDF]
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 K. S.C. Weber, L. B. Klickstein, and C. Weber Specific Activation of Leukocyte beta 2 Integrins Lymphocyte Function-associated Antigen-1 and Mac-1 by Chemokines Mediated by Distinct Pathways via the alpha Subunit Cytoplasmic Domains Mol. Biol. Cell, April 1, 1999; 10(4): 861 - 873. [Abstract] [Full Text]
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L. H. K. Lim, E. Solito, F. Russo-Marie, R. J. Flower, and M. Perretti Promoting detachment of neutrophils adherent to murine postcapillary venules to control inflammation: Effect of lipocortin 1 PNAS, November 24, 1998; 95(24): 14535 - 14539. [Abstract] [Full Text] [PDF]
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