Kj. Moore et al., TNF-ALPHA ENHANCES COLONY-STIMULATING FACTOR-1-INDUCED MACROPHAGE ACCUMULATION IN AUTOIMMUNE RENAL-DISEASE, The Journal of immunology, 157(1), 1996, pp. 427-432
The lpr mutation on the MRL background accelerates autoimmune nephriti
s in which macrophage (M phi) accumulation is prominent. Renal disease
is absent in other strains with lpr. TNF-alpha and CSF-1 are increase
d in the kidney of MRL-lpr mice with loss of renal function. We have e
stablished that CSF-1 can incite renal injury in mice with the lpr mut
ation, and M phi from the MRL strain hyper-respond to this growth fact
or. We hypothesized that TNF-alpha enhanced the M phi response to CSF-
1 in MRL-lpr mice. We now report that TNF-alpha enhanced CSF-1-induced
bone marrow M phi proliferation in MRL-lpr mice, and not in congenic
MRL +/+, normal C3H +/+ and BALB/c, or another strain with lpr(C3H-lpr
). Using a gene transfer approach to deliver CSF-1 together with TNF-a
lpha into the kidney, we evaluated the impact on renal injury. Tubular
epithelial cells genetically modified to produce CSF-1 (CSF-1-TEC) an
d TNF-alpha (TNF-TEC) placed under the renal capsule caused a greater
accumulation of M phi in the implant site than CSF-1-TECs alone in MRL
-lpr, but not MRL +/+ mice. We noted in tissues adjacent but not dista
l to the implanted TECs, an increase in M phi in the interstitium and
surrounding glomeruli of MRL-lpr but not MRL +/+ mice. This indicated
that CSF-1 and TNF-alpha released by TECs were responsible for promoti
ng renal pathology. Taken together, these data suggest that the simult
aneous expression of TNF-alpha and CSF-1 in the MRL-lpr kidney fosters
M phi accumulation. We speculate that the increase in M phi in the ki
dney in response to CSF-1 and TNF-alpha is responsible for the rapid t
empo of autoimmune renal injury in MRL-lpr mice.