Hobbs, Josie Anna Rose; (2003) An investigation into the in vitro and in vivo function of murine MRP-14 (S100A9). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

MRP-14 and its heterodimeric partner, MRP-8 are highly expressed in neutrophils and monocytes where they constitute 40% and 1% of the total cytosolic protein respectively. They are both low molecular weight proteins that belong to the S100 family of Ca2+ -binding proteins. Using the air pouch model of inflammation it has been demonstrated that recombinant murine MRP-14 (rMRP-14) is a potent chemoattractant for myeloid cells in vivo (May, 1999). While rMRP-14 did not directly cause chemotaxis or activation of myeloid cells in vitro, it caused a rapid elevation in the levels of cytokines in air pouch exudate, suggesting that rMRP-14 causes leukocyte influx via an indirect mechanism. As a control for endotoxin involvement, an air pouch experiment was performed using LPS insensitive mice. rMRP-14 did not produce an influx of cells. In addition, picogram levels of LPS, equivalent to the level of endotoxin contaminaton in rMRP-14, induced similar chemokines to rMRP14 in the air pouch. Therefore it is likely the effect of rMRP-14 in vivo is due to endotoxin contamination. Myeloid cells from MRP-14-/- mice were characterised. MRP-8 mRNA, but not protein, was present in these cells, suggesting that the stability of MRP-8 protein is dependent on MRP-14 expression. A compensatory increase in other proteins was not detected and myeloid cell development was unaffected in MRP-14-/- mice. MRP-14-/- neutrophils had a reduced Ca2+ flux in response to suboptimal levels of MIP-2. The ability of MRP-14-/- cells to perform chemotaxis, apoptosis or superoxide burst was unaffected. In an in vivo model of pneumonia, MRP-14-/- mice were less able to contain the infection than MRP-14+/+ mice. It is proposed that MRP-14 may not be dispensible for all myeloid cell functions. The role of MRP-8 during embryonic development was also investigated. MRP-8 was expressed by cells of both maternal and fetal origin. MRP-14-/- mice expressed reduced levels of MRP-8 and developed normally. This is in contrast to MPR-8-/- mice that die in utero (Passey et al., 1999a). Therefore, MRP-8 appears to play an essential function during development that is independent of MRP-14.

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