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E. C. Johnson, T. A. Doser, J. A. Dyck, W. S. Lambert, Y. Guo, W. O. Cepurna, J. C. Morrison; Differential Regulation of Interleukin 6-Type Cytokines in Early Elevated Intraocular Pressure (IOP)-Induced Optic Nerve Head (ONH) Injury. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2750.
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Using a rat glaucoma model and microarray analysis, we found that the gene expression changes in the ONH that accompany early injury due to elevated IOP are dominated by the upregulation of the cell cycle, as well as cytoskeletal, adhesion and extracellular matrix gene classes. Two cytokines with greatly increased expression levels in early ONH injury are interleukin 6 (IL6, 15.5 fold) and leukemia inhibitory factor (LIF, 5.4 fold), both IL6-type cytokines that signal via janus kinase (JAK) pathways. Here we examine the expression of other IL6-type cytokines, JAK-STAT signaling pathway components and potential downstream target genes.
We used episcleral vein injection of hypertonic saline to sclerose aqueous outflow pathways and produce elevated IOP to model glaucoma in rats. Retrobulbar optic nerve cross sections were graded for axon degeneration. ONH mRNA levels were determined in three ONH groups: controls, early injury (<15% axon loss, N=20), and advanced injury (>15% axon loss, N=24), utilizing microarrays and qPCR with statistical significance determined by Significance Analysis of Microarrays (SAM) and ANOVA (p<0.05).
By qPCR, we found that early injury significantly alters the mRNA levels of the IL-6 type cytokines, cardiotrophin-like factor 1 (CTLF1, 257±47% of control values) and ciliary neurotrophic factor (CNTF, 40±7%). Levels of other IL6-type cytokines are unchanged or not detected. IL6R alpha, the specific IL6 receptor, is unchanged while levels of the common receptor for LIF, CNTF and CTLF, LIFR, are decreased to 35±11%. Other JAK-STAT genes upregulated in early ONH injury are JAK1 (126%), JAK2 (146%), transcription factor STAT3 (141%), feedback inhibitors SOCS3 (372%) and SOCS4 (175%) as well as potential target genes: tissue inhibitor of metalloproteinases (TIMP1, 365%), alpha-2-macroglobulin (A2m,207%), FOS (206%) and heme oxygenase 1(Hmox1, 186%).
Altered IL6-type cytokine expression by astrocytes, retinal microglia and vascular cells can be produced by mechanical stress, such as that generated by elevated IOP. This study provides evidence that cytokines IL6, LIF, CNTF and CTLF and their signaling pathway components play important roles in early tissue responses to mechanical and other stresses that are induced in the ONH by elevated IOP exposure.
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