NK1.1 cells downregulate murine endotoxin-induced uveitis following intraocular administration of interleukin-12

Abstract

To evaluate the role of IFN-γ (interferon gamma) in IL-12- (interleukin-12)-induced inhibition of the inflammatory response in the eye during endotoxin-induced uveitis (EIU). C57BL/6 wild type mice and IFN-γ-deficient (GKO) mice were injected with 250 μg of Salmonella typhymurium endotoxin as a model for EIU. Animals were then injected intraocularly with 100 ng of rIL-12 or the equivalent volume of Phosphate-buffer saline (PBS). Histopathologic grading of disease was performed 12, 36 and 72 h after endotoxin injection. Chemokine mRNA expression in the eye was evaluated by reverse transcriptase-polymerase chain reaction. Depletion of NK1.1+ cells in vivo was performed using a PK136 antibody. Depletion of IFN-γ was performed using the R4-6A2 antibody. C57BL/6 mice treated with rIL-12 intraocularly were protected from the development of EIU. Neutralization of IFN-γ with a monoclonal antibody abrogated such protection. The IL-12 protective effects were lost in NK1.1-depleted mice. Intraocular IL-12 decreased the expression of keratinocyte-derived chemokines (KC) gene but had no effect on macrophage inflammatory protein (MIP-2) gene. The protective effect of IL-12 during EIU occurs through production of IFN-γ by NK1.1+ cells. IL-12-induced higher levels of IFN-γ are also correlated with lower expression of the chemokine KC, resulting in diminished attraction of neutrophils to the inflammatory site.