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(American Journal of Pathology. 2007;170:1241-1257.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060236

Protein Kinase C{zeta} (PKC{zeta}) Regulates Ocular Inflammation and Apoptosis in Endotoxin-Induced Uveitis (EIU)

Signaling Molecules Involved in EIU Resolution by PKC{zeta} Inhibitor and Interleukin-13

Yvonne de Kozak*, Boubaker Omri*{dagger}, Justine R. Smith*, Marie-Christine Naud*, Brigitte Thillaye-Goldenberg* and Patricia Crisanti*

From INSERM U598, Centre Biomedical des Cordeliers,* Université René Descartes, Paris; and Université Pierre et Marie Curie,{dagger} Paris, France

We show that inhibitory effect of interleukin-13 on endotoxin-induced uveitis in the Lewis rat is dependent on signaling activity of protein kinase C{zeta} (PKC{zeta}). To understand the effect of interleukin-13 or PKC{zeta} inhibitor treatment, the activation status of rat bone marrow-derived macrophages was studied in vitro. At 6 hours, lipopolysaccharide-stimulated macrophages produced tumor necrosis factor-{alpha} (TNF-{alpha}) with nuclear factor {kappa}B (NF-{kappa}B)/p65 expression. Treatment led to absence of NF-{kappa}B/p65 expression and low levels of TNF-{alpha}, suggesting accelerated inactivation of macrophages. At 24 hours after lipopolysaccharide stimulation, nuclear NF-{kappa}B/p65 decreased and nuclear NF-{kappa}B/p50 increased, associated with nuclear BCL-3 and a low level of TNF-{alpha}, indicating onset of spontaneous resolution. Treatment limited PKC{zeta} cleavage, with expression of nuclear NF-{kappa}B/p50 and BCL-3 and low nuclear NF-{kappa}B/p65 promoting macrophage survival, as evidenced by Bcl-2 expression. At 24 hours, intraocular treatment decreased membranous expression of PKC{zeta} by ocular cells, reduced vascular leakage with low nitric-oxide synthase-2 expression in vascular endothelial cells, and limited inflammatory cell infiltration with decreased intraocular TNF-{alpha}, interleukin-6, and nitric-oxide synthase-2 mRNA. Importantly, treatment decreased nuclear NF-{kappa}B/p65, increased transforming growth factor-ß2, and reduced caspase 3 expression in infiltrating macrophages, implying a change of their phenotype within ocular microenvironment. Treatment accelerated endotoxin-induced uveitis resolution through premature apoptosis of neutrophils related to high expression of toll-like receptor 4 and caspase 3.




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