| Abstract|| |
Interferon beta (IFNβ) is used in the therapy of multiple sclerosis (MS), which develops from the activation of autoreactive T lymphocytes against peptides of myelin basic protein. IFNβ was demonstrated to have beneficial effects in experimental models of glomerulonephritis (GN), such as decreasing proteinuria via Il-10 release. T helper (Th-1) lymphocyte responses are reduced, the actions of metalloproteinase (MMP9) are suppressed, and the functions of regulatory T cells are promoted. In concept, IFNI3 therapy might be beneficial in patients with life threatening forms of GN, such as Goodpasture's syndrome or vasculitis. Further research is warranted to study the effect of IFNβ on GN in clinical settings.
|How to cite this article:|
Wardle E N. Interferon-Beta for Glomerulonephritis?. Saudi J Kidney Dis Transpl 2007;18:333-6
| Introduction|| |
Interferon beta (IFNβ) is licensed for use in the therapy of multiple sclerosis (MS), which develops from the activation of autoreactive T lymphocytes against peptides of myelin basic protein, the principal component of the myelin sheath of nerve axons. Consequently, autoreactive T cells destroy the blood-brain barrier and the brain matrix, which results in an influx of associated inflammatory and immune cells into the brain.
IFNβ therapy usually results in a rise of serum levels of interleukin 10 (Il-10), which is an immunosuppressive cytokine.  Il-10 inhibits the activation of T cells, monocytes, and macrophages, and promotes suppression by T regulating autoimmune leukokine (TRAIL).  In view of its properties, Il-10 is thought to protect against autoimmunity. 
Accordingly, it is not surprising that the potential of therapy with IFNβ has been explored in various experimental models of glomerulonephritis (GN), even though it is recognized that TLR4 stimulation in GN by immune complexes results in "delayed response" formation of IFNβ. This increases macrophage formation of nitric oxide species (iNOS) and interleukin 12, an inflammation promoter. 
In 2005, Schwarting et al  reported on the benefits of IFNβ therapy in the autoimmune lupus of MRL-lpr mice. IFNβ was administered in the mice with either mild lupus nephritis or advanced disease. The results were very encouraging, for there was a decrease of leukocyte infiltration of the kidneys, a decrease of intra-renal IgG3 antibody, and a reduction of production of renal cytokines such as IFNγ and tissue necrotizing factor (TNFα).
More recently, research groups in the UK have assessed the effects of IFNβ in models of experimental GN.  Recombinant IFNβ (6 x 10 5 units per day) administered to WKY rats with nephrotoxic nephritis resulted in an 80% reduction of proteinuria at day 14. The numbers of proliferating cells within the glomeruli were reduced by 40%, despite the increase of CD8 T cells by 40% that is expected in nephrotoxic nephritis. Formation of alpha-smooth muscle actin (SMA) in these glomeruli was reduced. In Lewis rats with anti-Thy1 GN, there was a similar reduction of proteinuria, numbers of glomerular and interstitial cells, and the expression of αSMA. In an experiment that used monolayers of cultured cells (endothelial cells or podocytes), it was demonstrated how IFNβ decreased the trans-layer passage of albumin. These impressive findings in experimental settings prompted more research to elucidate the mechanism of action for IFNβ on GN.
| The Immune Suppressor Actions of IFNβ|| |
Most research into the immune effects of IFNβ has focussed on experimental encephalomyelitis, which is the equivalent of human MS. Teige et al  explored the effects of IFNβ on CNS antigen presenting cells and found that they were suppressed. It has been known for some time that IFNβ blocks the expression of MHC class II antigens that are required for the stimulation of CD4 T helper (Th) cells through the dendritic cells (DCs) in the CNS.  Furthermore, IFNβ therapy suppresses Th-1 lymphocytes through the action of Il-10 and enhances the expression of TRAIL on anti-CD3 activated T cells.  TRAIL and its receptors belong to the TNFa superfamily of cytokines that seems to mediate many of the antiviral, antitumor, and anti-inflammatory actions of the type I α and β IFNs.  Type I IFNs cause neutrophils and monocytes to release a soluble form of TRAIL. TRAIL supports the release of nitric oxide by endothelial cells and counteracts the ability of TNFα to promote adhesion of leucocytes to endothelial cells.
IFNβ directly inhibits the release of Il-12 that is required for Th-1 cell and indirectly through Il-10 stimulation in the peripheral blood mononuclear cells. , Moreover, using astroglioma cells, Nozell et al  demonstrated how IFNβ could also inhibit transcription of the Il-8 gene, which is a chemokine that recruits migrating neutrophils and other leucocytes to inflammatory sites. Accordingly, IFNβ could be used to control difficult cases of vasculitis or treat SLE exacerbations in which there is release of Il-12 and Il-8. 
Other actions of IFNβ are yet to be revealed, considering that IFNβ acts mostly by promoting the anti-inflammatory actions of Il-10.  Whenever Il-10 predominates, there is a release of decoy receptors for chemokine receptors (CCR), CCR 1 for migration inhibitory protein (MIP1α), CCR2 for migration controlling protein (MCP-1), and CCR5 for MIP-1β. Therefore, the suppression of these chemokines by IFNβ inhibits the monocytemacrophage-mediated inflammation such as that found in MS. In contrast, IFNβ has weak anti-apoptotic properties towards neutrophils via the stimulation of Il-2.  A third action of IFNβ is the inhibition of the metalloproteinase MMP-9 (gelatinase B), which is an amplifier of immune reactivity within the inflammatory foci.  In GN, MMP-9 is detectable in mesangial cells and in infiltrating neutrophils. A fourth action of IFNβ is the attenuation of the T cell activating effects of mast cells, through promotion of Il-10 and reduction of TNFα. 
Finally, IFNβ has growth inhibitory actions on cells; it was found to downregulate the expression of c-Myc and restrain cellular proliferation in leukemias.  This finding corresponds with the observations of Satchell et al.  The ability of IFNI3 to cause Go/G1 growth arrest of cell cycles was previously demonstrated.  The exact mechanism by which IFNβ causes the downregulation of cMyc are still not completely illustrated. 
In conclusion, IFNβ was demonstrated to have beneficial effects in experimental models of GN, such as decreasing proteinuria via Il-10 release. Th-1 lymphocyte responses are reduced, the actions of MMP9 are suppressed, and the functions of regulatory T cells are promoted. In concept, IFNβ therapy might be beneficial in patients with life threatening forms of GN, such as Goodpasture syndrome or vasculitis. Further research is warranted to study the effect of IFNβ on GN in clinical settings.
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E Nigel Wardle
London NW1 8JS
Source of Support: None, Conflict of Interest: None