Newton, Rebecca A.; (1997) A role for S100 proteins, MRP-8 and MRP-14 in leukocyte adhesion. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Migration inhibitory factor related protein (MRP)-8 and MRP-14 are S100 proteins primarily expressed by circulating human monocytes and neutrophils. In vivo MRP-8 and MRP-14 exist as a heterodimer (MRP-8/14) and represent ~40% of neutrophil cytosolic protein (~1% in monocytes). MRP-8/14 is also known to be expressed on the surface of neutrophils and monocytes and MRP-8 and MRP-14 have been detected in the extracellular environment. Despite their relative abundance and known expression patterns, no definitive function for the human proteins existed, to date. Previous results from our laboratory show extracellular localisation of MRP-8/14 on endothelium adjacent to marginating neutrophils and monocytes. This observation stimulated an investigation into the role of MRP-8/14 in neutrophil adhesion and transmigration. Initial experiments using purified native material indicated that MRP- 8/14 proteins were unable to stimulate neutrophil adhesion. Further analysis, with individual recombinant proteins, revealed that only MRP-14 could induce neutrophil adhesion, mediated by the β2 integrin Mac-1. MRP-8 did not induce any adhesion, but was able to inhibit the adhesion induced by MRP-14 through the formation of the heterodimer. MRP-14 was not able to induce subsequent transmigration of neutrophils, nor was it able to activate other neutrophil effector functions, such as changes in cell surface receptor expression, exocytosis, respiratory burst or Ca2+ flux. Instead, MRP-14 binds to a discrete G protein-coupled receptor on the neutrophils generating signals leading only to the activation of Mac-1. MRP-14 also bound to T lymphocytes and similarly induced Mac-1 activation. In addition, MRP-14 was also able to activate β1 integrin adhesion to fibronectin by these cells. Thus, it appears that MRP-14 by binding to its receptor is able to directly activate integrins allowing leukocyte adhesion. This results represent the first description of a function for MRP-8 and MRP-14 and suggest MRP-14 as an in vivo candidate of integrin activation resulting in leukocyte adhesion to endothelium.

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