JAK3-STAT pathway blocking benefits in experimental lupus nephritis.
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.



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.



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.



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.
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Èlia
È
Ripoll
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Laura
L
de Ramon
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Juliana
J
Draibe Bordignon
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Ana
A
Merino
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Nuria
N
Bolaños
Departament d'Anatomia Patològica, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Montse
M
Goma
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Josep M
JM
Cruzado
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain.
Josep M
JM
Grinyó
Laboratori 4120. Nefrologia Experimental, 4a Planta Pavelló Govern, Universitat de Barcelona. Campus Bellvitge, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL). Departament de Nefrologia, Hospital Universitari de Bellvitge, E-08907 L'Hospitalet, Barcelona, Spain. 15268jta@comb.cat.
Juan
J
Torras
D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008181:Lupus Nephritis / Q000473:pathology*; D051379:Mice; D008814:Mice, Inbred NZB; D010880:Piperidines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects
D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D050791:STAT Transcription Factors; C479163:tofacitinib; D053616:Janus Kinase 3
Autoimmunity; Glomerulonephritis; JAK3 inhibitor; Kidney infiltrate; Lupus nephritis