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S.J. Curnow, K.M. Wloka, D. Scheel-Toellner, S. Rose-John, V. Savant, K. Raza, M. Salmon, P.I. Murray; The Role of IL-6/IL-6R Trans-Signalling in the Inhibition of Growth Factor Deprivation-Induced Lymphocyte Apoptosis in Uveitis . Invest. Ophthalmol. Vis. Sci. 2003;44(13):674.
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Purpose: Active induction of apoptosis of inflammatory cells has been shown to be central to ocular immune privilege. We previously reported that the inflammatory ocular microenvironment in uveitis inhibits growth factor deprivation-induced apoptosis of lymphocytes. In this study we investigated the anti-apoptotic role of soluble IL-6/IL-6R complexes in this process. Methods: Aqueous humour (AqH) was collected from patients with untreated active uveitis and non-inflammatory controls. An in vitro culture system was used to study the effect of AqH on growth factor deprivation-induced apoptosis. Apoptosis was measured by analysis of mitochondrial membrane potential. IL-6 and sIL-6R were measured in AqH using multiplex bead immunoassays. Results: Growth factor deprivation-induced apoptosis of CD4+ T cells in vitro was profoundly inhibited by uveitis but not control AqH. Levels of IL-6 and sIL-6R in uveitis AqH correlated with the inhibition of apoptosis by these fluids (p=0.001 and p=0.005, respectively). Recombinant IL-6 alone was unable to inhibit growth factor deprivation-induced apoptosis of CD4+ T cells in vitro, consistent with the down-regulation of IL-6R on activated lymphocytes. However, apoptosis was inhibited by a combination of recombinant IL-6 and sIL-6R, or a recombinant construct of IL-6 linked to the IL-6R (Hyper IL-6). Preliminary evidence suggests that the ability of uveitis AqH to inhibit apoptosis can be significantly reduced by an anti-IL-6R blocking antibody. Conclusions: Our results suggest that the inhibition of growth factor deprivation-induced apoptosis by uveitis AqH may be due to IL-6/IL-6R trans-signalling. The complex of IL-6 and sIL-6R could bind to the gp130 signalling molecule on the infiltrating lymphocytes leading to inhibition of apoptosis. This process may contribute to the accumulation of inflammatory cells and subsequent damage to ocular tissues.
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