Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.
BACKGROUND
In human glomerulonephritis, including immunoglobulin-A nephropathy (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is found to correlate with progressive renal injury. We have shown previously that polymeric IgA is capable of inducing MIF production in cultured human mesangial cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we examined whether IgA deposition and the subsequent renal injury can be ameliorated with anti-MIF treatment in an experimental murine model of IgAN.


METHODS
Glomerular IgA deposition was induced in 4-week-old BALB/c mice by intravenous injection of immune complexes consisting of dinitrophenyl-conjugated bovine serum albumin (DNP-BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg) or isotypic control antibody intravenously 2 h before the immune complexes administration. The mice were sacrificed 48 h after injection of DNP-IgA. Proteinuria and haematuria were determined and the kidneys were removed for histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on production of TGF-beta 1 by cultured mesangial cells was also examined.


RESULTS
IgA deposits were detected in glomeruli of all mice receiving the immune complexes while no glomerular deposit was detected in the control mice. Microscopic haematuria and mesangial hypercellularity were present in mice of the three experimental groups and were absent in the control group. Proteinuria was absent in all groups. Anti-MIF treatment also resulted in decreased renal expression of TGF-beta 1. Moreover, the reduction in TGF-beta 1 expression was confined mainly to glomerular mesangium. An in vitro culture experiment demonstrated that MIF increased TGF-beta 1 production in a time- and dose-dependent fashion. MIF-induced TGF-beta 1 synthesis was abolished by incubating cells with neutralizing antibody against MIF.


CONCLUSIONS
Our finding shows that anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-beta 1 expression in an experimental model of IgAN.
Leung
Joseph C K
JC
Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong.
Chan
Loretta Y Y
LY
Tsang
Anita W L
AW
Liu
Emily W L
EW
Lam
Man Fai
MF
Tang
Sydney C W
SC
Lai
Kar Neng
KN
D000818:Animals; D000911:Antibodies, Monoclonal; D015870:Gene Expression; D005922:Glomerulonephritis, IGA / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000502:physiology
D000911:Antibodies, Monoclonal; D008263:Macrophage Migration-Inhibitory Factors; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1