Target Cells for Macrophage Stimulating Protein

TARGET CELLS FOR MACROPHAGE STIMULATING PROTEIN 

Membrane activity is accompanied by cellular motility, characterized by extension and withdrawal of cell projections, unaccompanied by significant translational movement. Although this cellular motility program is initiated by MSP, it persists for at least 2 hr without a requirement for continuing MSP stimulation. This conclusion is based on the fact that MSP action is dependent on PI3K, and can be prevented by prior administration of the PI3K inhibitor wortmannin. However, once MSP induces the cellular motility pattern, addition of wortmannin has no effect. 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of 

In immunolocalization studies of ciliated epithelium, Ron was detected in nasal and bronchial epithelium and in normal oviduct (Sakamoto et al., 1997). Primary cultures of normal human bronchial epithelium expressed Ron as assessed by flow cytometry and bound MSP with a Kd of 0.5 nM. MSP caused tyrosine phosphorylation of the receptor. Ron and Met were both expressed in ciliated bronchial epithelium, the latter in a basolateral location, the former at the apical surface just below the base of the cilia. This led to the finding that MSP caused a transient increase of about 20% in the ciliary beat frequency of nasal mucosal cells. In view of Ron mRNA expression in sperm and MSP mRNA in epithelium of epididymis (Ohshiro et al., 1996), the authors suggest a possible role for MSP in sperm motility as well as in mucociliary transport. 

Ron protein was detected by immunolocalization on vascular endothelial cells in human dermis. The frequency of detection was higher in burn wounds than in normal skin (Nanney et al., 1998). HGF has been reported to be angiogenic. MSP is also angiogenic by the mouse cornea assay (Y. Cao and E. J. Leonard, unpublished data). 

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VIII. Target Cells for Macrophage Stimulating Protein... 

VIII. TARGET CELLS FOR MACROPHAGE STIMULATING PROTEIN... 

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