May, Richard David; (1999) An investigation into the function of two murine S100 proteins, MRP-8 and MRP-14. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neutrophils are the fastest responding leukocytes in an inflammatory response. Two major components (up to 45%) of the neutrophil's cytosolic protein are MRP-8 and MRP-14. MRP-8 and MRP-14 are members of the S100 family of calcium binding proteins, designated MRP-8 and MRP-14, respectively. They have tissue specific expression and are found in myeloid cells and specialised epithelium. Previous work from this laboratory suggests a potential role for the proteins in inflammation. Investigation of recombinant human MRP-8 and MRP-14 (rHuMRP-8 or 14) showed rHuMRP-14 to be a novel activator of the p2 integrin, Mac-1 on neutrophils, causing ligation of fibrinogen. rHuMRP-8 inhibited this stimulated adhesion by formation of a rHuMRP-8/14 heterodimer. This thesis aims to further investigate the function of these enigmatic proteins by analysing the murine homologues, also known as MRP-8 and MRP-14. rMuMRP-8 is reported to be a potent (10-12M) neutrophil and monocyte chemoattractant. rMuMRP-14 was found to share functional similarity with rHuMRP-14 by causing neutrophil adhesion without causing chemotaxis or respiratory burst. rMuMRP-14 was also found to be functionally dissimilar to rHuMRP-14 by causing cell activation of resting peripheral cells, but not activated, pre-migrated cells, as measured by intracellular calcium flux. In vivo, in an air pouch model of inflammation, rMuMRP-14 caused profound neutrophil and monocyte infiltration with a peak response at 6 hours with a 50ug dosage. Taken together, these data suggest that rMuMRP-14 is a direct activator of cell adhesion but an indirect activator of cell migration. Protein investigation was further investigated by the creation of knockout mice. Both muMRP-8 and muMRP-14 deficient animals were healthy and fertile with grossly normal neutrophils. The mice await detailed phenotyping. In summary, muMRP-8 and muMRP-14 have functional extracellular roles in inflammation but their absence affects neither mouse viability nor gross neutrophil morphology.

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