CULTURED MESANGIAL CELLS FROM AUTOIMMUNE MRL-LPR MICE HAVE DECREASED SECRETED AND SURFACE M-CSF

M-CSF has been implicated in the pathogenesis of lupus nephritis in MRL-lpr mice. We recently reported persistently high levels of serum M-CSF in MRL-lpr mice as early as one week of age, not present in normal mice including C3H mice. In addition, M-CSF transcripts in MRL-lpr renal cortex increased with an increase in the severity of nephritis. Because glomerular mesangial cells (MC) secrete M-CSF, we investigated whether cultured MRL-lpr MC secrete more M-CSF than C3H MC. Paradoxically, unstimulated MRL-lpr MC secreted substantially less M-CSF than C3H MC [26 +/- 11 vs. 109 +/- 7 colony forming units (CFU)]. We then explored whether MC could express membrane bound M-CSF. We detected a 31 kDa form of membrane M-CSF on both MRL-lpr and C3H MC. Fewer MRL-lpr MC than C3H MC (24 +/- 5% vs. 78 +/- 5%) expressed membrane M-CSF. Furthermore, the increase in the mean channel log fluorescence intensity on MRL-lpr MC was considerably less than in C3H MC, indicating a lower density of M-CSF on MRL-lpr MC. Because our prior studies established that MRL-lpr kidneys have enhanced expression of TNF-alpha, we stimulated cultured MC with TNF-alpha. TNF-alpha increased M-CSF secretion by stimulated MRL-lpr by twofold over unstimulated MRL-lpr MC, but did not increase M-CSF in C3H MC. In addition, M-CSF secretion was modestly greater in stimulated MRL-lpr MC compared to stimulated C3H MC. In conclusion, this is the first report of membrane M-CSF detectable on cultured MC. These studies note that despite higher circulating M-CSF and renal M-CSF transcripts in MRL-lpr mice, cultured MRL-lpr MC have lower basal secreted and membrane bound M-CSF than cultured C3H MC. TNF-alpha increases secretion of M-CSF by MRL-lpr MC, but does not enhance membrane M-CSF. Since these studies are restricted to a comparison of MC from autoimmune and normal mice in vitro, we are engaged in further studies to evaluate in vivo production of M-CSF by MC and the importance of this growth factor in renal injury.