Cyclin-dependent kinase inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus.
OBJECTIVE
To examine whether the cyclin-dependent kinase (CDK) inhibitor seliciclib ameliorates autoimmune nephritis in (NZB x NZW)F(1) mice.


METHODS
In experiment 1, NZB x NZW mice received seliciclib (100 mg/kg or 200 mg/kg) or vehicle by gavage, beginning at age 2 months and ending at 8 months of age. In experiment 2, seliciclib (200 mg/kg) was administered alone or combined with low-dose methylprednisolone, starting at age 5 months, when immune complex deposition in the kidney had already occurred. Animals were followed up until all vehicle-treated mice died. In 2 additional groups of NZB x NZW mice treated with seliciclib or vehicle from 2 months of age until 5 months of age, splenocytes were isolated and tested ex vivo for T cell and B cell activity.


RESULTS
Seliciclib, given at an early phase of disease, prolonged survival, delayed the onset of proteinuria and renal function impairment, and protected the kidney against glomerular hypercellularity, tubulointerstitial damage, and inflammation. Combining seliciclib with low-dose methylprednisolone in mice with established disease extended the lifespan and limited proteinuria and renal damage more than treatment with either agent alone. Seliciclib limited immunologic signs of disease, reducing glomerular IgG and C3 deposits and levels of serum anti-DNA antibodies. Moreover, it inhibited ex vivo T cell and B cell proliferative responses to polyclonal stimuli. T cell production of interferon-gamma and interleukin-10 and B cell release of IgG2a were reduced by treatment with seliciclib.


CONCLUSIONS
These findings suggest that CDK activity may be a useful target in the treatment of systemic lupus erythematosus. A direct immunomodulatory action of seliciclib on T cells and B cells may be one of the mechanisms underlying the beneficial effects.
Zoja
Carla
C
Mario Negri Institute for Pharmacological Research, Bergamo, Italy. zoja@marionegri.it
Casiraghi
Federica
F
Conti
Sara
S
Corna
Daniela
D
Rottoli
Daniela
D
Cavinato
Regiane A
RA
Remuzzi
Giuseppe
G
Benigni
Ariela
A
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects / Q000502:physiology; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008136:Longevity / Q000187:drug effects* / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008775:Methylprednisolone / Q000627:therapeutic use; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use*; D000077546:Roscovitine; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D000893:Anti-Inflammatory Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D008775:Methylprednisolone