The human S100 protein MRP-14 is a novel activator of the beta 2 integrin Mac-1 on neutrophils.
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 (approximately 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 beta 2 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 beta 2 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.
Newton
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RA
Leukocyte Adhesion Laboratory, Imperial Cancer Research Fund, London, United Kingdom.
Hogg
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N
D000276:Adjuvants, Immunologic / Q000502:physiology; D000943:Antigens, Differentiation / Q000378:metabolism / Q000502:physiology*; D001665:Binding Sites / Q000276:immunology; D018821:CD18 Antigens / Q000378:metabolism* / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D040501:Calgranulin A; D040502:Calgranulin B; D002448:Cell Adhesion / Q000276:immunology; D048429:Cell Size / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute; D016177:Macrophage-1 Antigen / Q000378:metabolism* / Q000502:physiology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D011971:Receptors, Immunologic / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000943:Antigens, Differentiation; D018821:CD18 Antigens; D002135:Calcium-Binding Proteins; D040501:Calgranulin A; D040502:Calgranulin B; D016177:Macrophage-1 Antigen; D011971:Receptors, Immunologic