title: IP-10 and Mig production by glomerular cells in human proliferative glomerulonephritis and regulation by nitric oxide.
abstract: High levels of expression of mRNA and protein for the chemokines interferon-gamma (IFN-gamma)-inducible protein of 10 kD (IP-10) (CXCL10) and the monokine induced by IFN-gamma (Mig) (CXCL9) were observed, by using in situ hybridization and immunohistochemical analyses, in kidney biopsy specimens from patients with glomerulonephritis (GN), particularly those with membranoproliferative or crescentic GN, but not in normal kidneys. Double-immunostaining or combined in situ hybridization and immunohistochemical analyses for IP-10, Mig, and proliferating cell nuclear antigen (PCNA) or alpha-smooth muscle actin (alpha-SMA) revealed that IP-10 and Mig production by resident glomerular cells was a selective property of glomeruli in which mesangial cells demonstrated active proliferation. IP-10 and Mig mRNA and protein were also expressed by primary cultures of human mesangial cells and human visceral epithelial cells after stimulation with IFN- gamma or with IFN-gamma plus tumor necrosis factor-alpha (TNF-alpha) (which produced greater stimulation). The induction of IP-10 and Mig mRNA and protein expression by IFN-gamma plus TNF-alpha was strongly inhibited by nitric oxide (NO) donors, such as sodium nitroprusside or S-nitroso-N-acetylpenicillamine, but not by cGMP analogues. Electrophoretic mobility shift assays demonstrated that NO donors repressed IP-10 gene transcription induced by IFN-gamma plus TNF-alpha through the inhibition of NF-kappaB activation. These data demonstrate that resident glomerular cells in kidneys of patients with proliferative GN produce large amounts of IP-10 and Mig, which may play important pathogenic roles in this disease. These data also indicate that the production of IP-10 and Mig by human mesangial cells can be downregulated by NO donors through cGMP-independent inhibition of NF-kappaB activation.
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lazzeri
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lasagni
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Mavilia
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Beltrame
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Francalanci
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Rotondi
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Maurenzig
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Galli
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Salvadori
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Maggi
authors.affiliation: *Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
mesh_terms: D002478:Cells, Cultured; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism*; D007678:Kidney Glomerulus; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014781:Viscera / Q000378:metabolism
chemical_list: C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D006152:Cyclic GMP