INTERCELLULAR-ADHESION MOLECULE-1 AND TUMOR-NECROSIS-FACTOR-ALPHA EXPRESSION IN HUMAN GLOMERULONEPHRITIS

The relationship between renal expression of intercellular adhesion mo lecule-1 (ICAM-1), glomerular hypercellularity, renal function and ren al tumour necrosis factor-alpha (TNF-alpha) expression was examined by immunohistochemistry staining in 64 cases of human glomerulonephritis . Glomerular anti-ICAM-1 antibody staining was increased in most cases of IgA nephropathy and lupus nephritis, but was unchanged compared to normal in membranous nephropathy and minimal change disease, and redu ced in glomerular sclerosis. However, when taken together, patients wi th mild or no glomerular hypercellularity (group A) showed normal ICAM -1 expression, those with moderate to severe hypercellularity (group B ) had increased glomerular ICAM-1 expression (P < 0.001), while those with glomerular sclerosis (group C) had reduced glomerular ICAM-1 expr ession. Patients in groups B and C also showed a significant increase in tubular ICAM-1 expression (P < 0.01) and interstitial infiltration of ICAM-1(+) cells (P < 0.001). Indeed, tubular ICAM-1 expression corr elated with decreased creatinine clearance (r = -0.352; P < 0.05). In situ hybridization demonstrated that increase in tubular ICAM-1 staini ng was due to de novo gene expression, rather than absorption of solub le ICAM-1 from the lumen. Focal expression of tumour necrosis factor-a was seen in areas of leucocyte infiltration and strong ICAM-1 express ion. Indeed, TNF-alpha staining correlated with increased renal ICAM-1 expression in both glomerular and tubulointerstitial compartments (r = 0.81; P<0.01). To confirm that TNF-alpha can directly stimulate rena l ICAM-1 expression, TNF-alpha was shown to transiently increase ICAM- 1 mRNA synthesis for 4-8 h and cause a progressive increase in ICAM-1 protein on the surface of cultured human mesangial cells. In summary; (i) increased glomerular ICAM-1 expression was restricted to cases of moderate to severe hypercellularity; (ii) tubular ICAM-1 expression co rrelated with both creatinine clearance and interstitial infiltration of ICAM-1(+) cells; and (iii) TNF-alpha expression was shown to correl ate with the degree of renal ICAM-1 expression, suggesting that local TNF-alpha plays an important role in the up-regulation of ICAM-1 in hu man glomerulonephritis.