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Background: A loss of intestinal glycosaminoglycans (GAGs) has been shown in inflammatory bowel diseases (IBD). Since GAGs are involved in the regulation of renal protein filtration and GAGs disruption is associated with anionic proteinuria, we examined whether changes in the selectivity of renal protein filtration occur in IBD., Methods: From 46 patients with IBD (17 with Crohn's disease (CD), and 29 with ulcerative colitis (UC)) and 21 healthy subjects, urine and serum samples were obtained. Albumin, total IgG and IgG(4) clearances were measured using sensitive methods. Serum p-ANCA and TNF-alpha were tested., Results: Median IgG(4) clearance was 0.041 ml/ min/10(-3) in patients with UC and 0.10 ml/ min/10(-3) in CD patients, both significantly higher than in controls (0.03 ml/min/10(-3)) (P<0.03). IgG(4) clearance was above the upper normal limit in 9/17 CD (53%) and in 10/29 UC (34.5%). Eighteen of 19 patients showing abnormal IgG(4) clearance were taking mesalazine. In patients on maintenance oral mesalazine, IgG(4) clearance was higher than that in patients off treatment (0.12 vs 0.03 ml/min/10(-3), P=0.04). No clinical/laboratory sign of renal dysfunction was documented in patients with altered IgG(4) clearance and maintained on mesalazine treatment., Conclusion: Renal protein charge permselectivity is impaired in 40% of patients with IBD with no overt proteinuria. Our data suggest that altered IgG(4) clearance may represent a subclinical marker of renal involvement in IBD.

IL-12 modulates Th1 immune response during chronic colitis. Mechanisms regulating IL-12 synthesis in human intestine are poorly understood. The aim of this study was to investigate the effect of IFN-gamma and PGE2 on lipopolysaccharide (LPS)-stimulated LPMC IL-12 production. Normal LPMC cultures were run in the presence or absence of IFN-gamma and/or PGE2 before LPS stimulation. To examine the role of endogenous PGE2 on LPS-stimulated IL-12 release, LPMC cultures were added of indomethacin before LPS stimulation. IL-12, IL-10 and IL-8 were measured by ELISA. No IL-12 was detected in either unstimulated or LPS-stimulated LPMC cultures. In contrast, LPMC released IL-8 (650 +/- 125 pg/ml) and IL-10 (75 +/- 25 pg/ml) in response to LPS. Treatment of LPMC with IFN-gamma facilitated LPS-stimulated IL-12, whereas it completely abrogated IL-10 production. IL-12 release by LPMC stimulated with IFN-gamma and LPS was significantly inhibited by exogenous IL-10. The addition of PGE2 to IFN-gamma-treated LPMC cultures inhibited in a dose-dependent manner LPS-induced IL-12 secretion. Furthermore, IL-12 was detectable (85 +/- 25 pg/ml) in the supernatants of LPMC cultures treated with indomethacin and LPS. In contrast to the effect on IL-12, PGE2 significantly augmented LPS-stimulated LPMC IL-10 production. However, the inhibition of IL-12 by PGE2 was only partially reversed by anti-IL-10. In a simplified model of LPS tolerance, we finally showed that monocyte-derived macrophages exhibited reduced IL-12 production after repeat LPS stimulation. In these cell cultures, indomethacin abrogated the induction of LPS desensitization. IFN-gamma and PGE2 modulate differently the LPMC responsiveness to LPS in terms of IL-12 synthesis.

: Antineutrophil-cytoplasmic-autoantibodies (p-ANCA) are strongly associated with ulcerative colitis (UC) and may represent an indicator of genetic susceptibility to UC. To further examine whether p-ANCA may serve as a genetic marker of UC we evaluated the frequency of p-ANCA in unaffected family members of UC from a defined geographic area. A total of 110 patients with UC and 90 unaffected family members (first- or second-degree relatives) were tested. Controls included: 58 Crohn's disease (CD) patients with 25 unaffected relatives and 52 irritable bowel syndrome (IBS) patients with 20 healthy family members. p-ANCA were detected by enzyme-linked immunoassay followed by immunofluorescence. p-ANCA were detected in 57 UC patients (51.8%). Six of 90 (6.6%) unaffected relatives were positive for p-ANCA and 4 of these were from two families. In 3 of 35 families the proband and at least one unaffected relative were p-ANCA-positive. In five families with more than one member affected by UC, p-ANCA were detected in 2 of 19 (10.5%) unaffected relatives. Six CD patients (10.3%) and one (1.9%) in the IBS group were positive for p-ANCA. One family member was positive in the CD family group and 1 was positive in the control family group. In the group of families recruited for this study, p-ANCA were not more frequent in unaffected relatives of UC patients than in controls, suggesting that at least in the geographic area considered for this study p-ANCA may not represent a definite subclinical marker of susceptibility for UC.