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Renal tubular epithelial cells (TEC) can express MHC class II molecules in vitro and in vivo. Their ability to also secrete cytokines and express adhesion molecules suggests a possible immune accessory role for TEC. We have previously documented that TEC process and present antigen to T cell hybridomas. However, engagement of the T cell receptor alone is sufficient to induce IL-2 secretion by T cell hybridomas. We now report that presentation of antigen by TEC to a CD4+ T cell clone results in functional inactivation of the T cells. Despite antigen-specific anergy, these T cells are viable and proliferate in response to IL-2. Furthermore, allogeneic antigen presenting cells were unable to restore the T cell proliferative response, suggesting that the mechanism(s) was not entirely costimulator-dependent.

In this study we examine the role of colony stimulating factor-1 (CSF-1) in the induction of lupus nephritis. The purpose of the study was to establish the relationship of CSF-1 to the prominent influx of macrophages (M phi) in the glomeruli of MRL-lpr mice with autoimmune lupus nephritis. The kidneys of MRL-lpr mice were examined before (< 12 weeks of age) and after (> 12 weeks of age) renal injury for CSF-1 transcripts by in situ hybridization. CSF-1 mRNA was detected at four weeks of age within glomeruli and increased with disease severity. To examine whether glomerular M phi (glom M phi) required CSF-1 we isolated M phi from the kidneys of MRL-lpr mice. Two types of glom M phi (with morphological and growth characteristics which correlated with the presence or absence of proteinuria) were isolated. Under CSF-1-free culture conditions, where the viability of glom M phi from proteinuric mice was maintained, glom M phi from pre-proteinuric mice were unable to survive. Neutralization of CSF-1 in the media reduced viability of pre-proteinuric glom M phi (5 to 6 x), while viability of proteinuric glom M phi was diminished < 1.5 x. Additionally, CSF-1 supplementation induced a 10 x proliferation of pre-proteinuric glom M phi when compared to CSF-1-free medium. In contrast, proteinuric glom M phi did not proliferate in response to CSF-1. These studies suggest that CSF-1 induces macrophage proliferation and differentiation within glomeruli and, in turn, renal injury.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor-alpha (TNF alpha) is a pleiotropic, pro-inflammatory peptide cytokine which promotes immune renal injury, and participates in T cell activation. It is produced by macrophages, T cells, and some non-hematopoietic cells, and is cytotoxic in picogram quantities. As renal tubular epithelial cells (TEC) bearing MHC class II (Ia) antigens and adhesion molecules (ICAM-1) can act as immune accessory cells, the ability of TEC to produce costimulatory cytokines could augment TEC accessory capacity in vivo. We report that transformed TEC express low levels of TNF alpha in response to LPS or IL-1 alpha as a secreted product and as a cytotoxic membrane associated molecule displayed on the cell surface. Surface labelling and immunoprecipitation studies of TEC detect a number of bands including a prominent 26 kD protein, which is the predicted size of TNF alpha precursor. TNF alpha mRNA transcripts were also detected by in situ hybridization in cortical tubules of C3H/FeJ mice injected with LPS, demonstrating the capacity of normal tubular epithelial cells to express TNF alpha in vivo. This report demonstrates for the first time the ability of kidney tubular cells to express TNF alpha protein and that membrane associated TNF alpha is not limited to hematopoietic cells. The function of small amounts of TNF displayed on the surface of tubular cells may be amplified by the abundance of these cells within the renal cortex, and may allow TEC to modulate immune responses within the kidney during inflammation.