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D. Shen, N. Tuaillon, J. Peterson, B. Lu, C. Chan; Lack of Ocular Response to Lipopolysaccharide in CCR-1 Deficient Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):720.
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Purpose: Chemokines are a large family of secreted proteins involved in regulating multiple steps in host inflammatory responses. CCR-1, one of the CC chemokine receptor, is expressed on neutrophils, monocytes, lymphocytes and eosinophils, and binds related chemokines to regulate T-cell activation and to recruit the immune cells to sites of inflammation. Endotoxin induced uveitis (EIU) in murine model is regulated by cytokine interactions that result in ocular inflammation. The goal of this study is to ascertain the role played by CCR-1 in the evolution of uveitis using the murine EIU model. Methods: Six repeated experiments were performed. EIU was induced in a total of 67 CCR-1 deficient (CCR-1-/-) and 61 wild type (C57Bl/6) mice by a single subcutaneous injection of 100 µg of Salmonella typhimurium lipopolysaccharide (LPS) in 0.1 ml PBS. The control groups (12 mice for each type) received PBS injection alone. All mice were sacrificed at 24 hours after injection. The eyes were collected for routine histology examination and RNA isolated for RT-PCR of ß-Actin, IL-6, IL-12, IFN-γ, RANTES and MIP-1α. Serum IL-6, IL-12, IFN-γ, MIP-1α and MIP-2 were measured using ELISA. Statistics was analyzed using StatView version 4.5. Results:EIU was significantly reduced in CCR-1-/- mice compared with wild type mice. The number of ocular inflammatory cells were 5.27±6.65 (mean±SD) in CCR-1-/- and 17.00±15.73 in C57Bl/6 mice, p<0.0001. In contrast, serum ELISA showed a higher level of IL-6, IL-12, IFN-γ, MIP-1α and MIP-2 in CCR-1-/- mice than that in C57Bl/6 mice. The results were IL-6, 113 34.7±15728.1 (pg/ml) vs 2335.9± 3122.1, p=0.01; IL-12, 1779.0±908.4 vs 647.9±536.7, p=0.008; IFN-γ, 5601.8±1029.5 vs 420.4±341.8, p=0.023; MIP-1α, 297.7±122.3 vs 115.0±47.0, p=0.073; MIP-2, 2099±1723.0 vs 1185.0±813.6, p=0.028. RT-PCR also showed a higher concentration of IL-6 mRNA and slightly higher concentration of other mRNA transcripts in CCR-1-/- than that in C57Bl/6 mice. Conclusions:Mice deficient in CCR-1 have defect of inflammatory cell recruitment and migration to infected site, and resulted reducing the number of inflammatory cells in the eye during EIU. The absence of CCR-1 may disturb the chemokine signaling and cytokine-chemokine networking in inflammation. The excess of chemokines may serve as feedback signals to initiate a cascade of immune response in EIU model. The mechanism of regulation of cytokines and chemokines in EIU is not clearly understood yet, continue research in this area might be helpful in the development of a new therapeutic strategy for human uveitis.
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