May 2007
Volume 48, Issue 13
ARVO Annual Meeting Abstract  |   May 2007
Suppression of Retinal Inflammation in Endotoxin-Induced Uveitis by the Kinase Inhibitor, PKC412
Author Affiliations & Notes
  • S.-M. Liao
    Ophthalmology, Novartis, Cambridge, Massachusetts
  • O. Deldago
    Ophthalmology, Novartis, Cambridge, Massachusetts
  • D. Yoo
    Ophthalmology, Novartis, Cambridge, Massachusetts
  • M. Keating
    Ophthalmology, Novartis, Cambridge, Massachusetts
  • B. Jaffee
    Ophthalmology, Novartis, Cambridge, Massachusetts
  • Footnotes
    Commercial Relationships S. Liao, Novartis, E; O. Deldago, Novartis, E; D. Yoo, Novartis, E; M. Keating, Novartis, E; B. Jaffee, Novartis, E.
  • Footnotes
    Support Novartis
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2637. doi:
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      S.-M. Liao, O. Deldago, D. Yoo, M. Keating, B. Jaffee; Suppression of Retinal Inflammation in Endotoxin-Induced Uveitis by the Kinase Inhibitor, PKC412. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2637.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose:: PKC412 has been shown to prevent retinal neovascularization. To investigate its possible role in retinal inflammation, we assessed the effects of PKC412 on retinal cytokine production and inflammatory cell migration in a murine model of endotoxin-induced uveitis(EIU).

Methods:: EIU was induced in C57Bl6 mice following intraperitoneal injection of 50 µg of LPS in 0.1 ml PBS. Either PKC412 or vehicle was administered via oral gavage one hour prior to LPS challenge. Four mice of each treatment group were euthanized 3 hours after LPS injection for cytokine analysis. Plasma and retina were collected. Protein extracts were prepared from retina samples and were analyzed using multiplex cytokine and chemokine assays. To determine retinal leukocyte infiltration, 6 mice per group were euthanized 24 hours post LPS injection. Eyes were collected and retinas were dissected for whole mount immuno-stainings of neutrophils (Gr-1) and macrophages (F4/80).

Results:: Three hours after induction of EIU, pro-inflammatory cytokines and chemokines (IL-6, KC, MCP-1, MIP-1alpha) were increased in both plasma and retina. A single oral administration of PKC412 resulted in significant dose-dependent reductions of IL-6, MCP-1, and MIP-1alpha. Twenty four hours post LPS induction, both neutrophils and macrophages were observed to migrate into the retina. At 100mpk of an oral PKC412, retinal leukocyte infiltration was decreased by greater than 90%.

Conclusions:: PKC412, a protein kinase inhibitor, blocked the development of EIU by preventing the production of IL-6 and the chemokines MCP-1, MIP-1, and RANTES, resulting in an inhibition of leukocyte recruitment into the retina. These data suggest that PKC412 inhibits TLR4 signaling to regulate gene expressions of monocyte chemoattractants.

Keywords: uveitis-clinical/animal model • drug toxicity/drug effects • retina 

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