IP-10 and Mig production by glomerular cells in human proliferative glomerulonephritis and regulation by nitric oxide.
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.
Romagnani
Paola
P
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Lazzeri
Elena
E
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Lasagni
Laura
L
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Mavilia
Carmelo
C
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Beltrame
Chiara
C
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Francalanci
Michela
M
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Rotondi
Mario
M
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Annunziato
Francesco
F
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Maurenzig
Lucia
L
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Cosmi
Lorenzo
L
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Galli
Grazia
G
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Salvadori
Maurizio
M
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Maggi
Enrico
E
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
Serio
Mario
M
*Department of Clinical Pathophysiology, Endocrinology Unit, Department of Internal Medicine, Immunoallergology Unit, Division of Nephrology and Dialysis, University of Florence, Florence, Italy.
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
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