JAK3-STAT pathway blocking benefits in experimental lupus nephritis.
BACKGROUND
Lupus nephritis (LN) is a complex chronic autoimmune disease of unknown etiology characterized by loss of tolerance against several self-antigens. Cytokines are known to be central players in LN pathogenesis. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is one important pathway that mediates signal transduction of several cytokines. In this study, we examined the pathogenic role of this pathway and how CP-690,550 treatment influences LN outcome.


METHODS
Six-month-old NZB/NZWF1 mice were divided into two different treatment groups: (1) control animals given vehicle treatment, cyclophosphamide, and mycophenolate mofetil treatment as positive controls of the therapy and (2) mice treated with CP-690,550, a JAK3 inhibitor. Mice were treated for 12 weeks. We evaluated renal function, anti-double-stranded DNA (anti-dsDNA) antibody, renal histology changes, kidney complement and immunoglobulin G (IgG) deposits, T-cell and macrophage infiltration, kidney inflammatory gene expression, and circulating cytokine changes.


RESULTS
CP-690,550 treatment significantly reduced proteinuria and improved renal function and histological lesions of the kidney. Compared with vehicle-treated animals, those undergoing CP-690,550 treatment showed significantly diminished anti-dsDNA antibody and complement component C3 and IgG deposition in glomeruli. We also observed a significant reduction of T-cell and macrophage infiltration. Kidney gene expression revealed a reduction in inflammatory cytokines and complement and related macrophage-attracting genes. Circulating inflammatory cytokines were also reduced with treatment.


CONCLUSIONS
On the basis of our results, we conclude that the JAK-STAT pathway is implicated in the progression of renal inflammation in NZB/WF1 mice and that targeting JAK3 with CP-690,550 is effective in slowing down the course of experimental LN. Thus, CP-690,550 could become a new therapeutic tool in LN and other autoimmune diseases.
['Ripoll|Èlia|È|', 'de Ramon|Laura|L|', 'Draibe Bordignon|Juliana|J|', 'Merino|Ana|A|', 'Bolaños|Nuria|N|', 'Goma|Montse|M|', 'Cruzado|Josep M|JM|', 'Grinyó|Josep M|JM|', 'Torras|Juan|J|']
D000818:Animals D004195:Disease Models, Animal D004797:Enzyme-Linked Immunosorbent Assay D005455:Fluorescent Antibody Technique D020869:Gene Expression Profiling D053616:Janus Kinase 3 D008181:Lupus Nephritis D051379:Mice D008814:Mice, Inbred NZB D010880:Piperidines D016133:Polymerase Chain Reaction D047428:Protein Kinase Inhibitors D011743:Pyrimidines D011758:Pyrroles D050791:STAT Transcription Factors D015398:Signal Transduction D059467:Transcriptome
Lupus nephritis Autoimmunity JAK3 inhibitor Glomerulonephritis Kidney infiltrate