Intraocular inflammatory diseases (uveitis) of noninfectious etiology comprise a large number of potentially sight-threatening disorders and several of them are characterized by elevated levels of intraocular interferon gamma (IFNgamma) and aberrant expression of MHC class II proteins in the eye. Studies of mouse models of uveitis indicate paradoxically, that depletion of systemic IFNgamma confers protection against posterior uveitis. Furthermore, induction of IFNgamma secretion in the eye by intraocular injection of IL-12 was found to exacerbate anterior uveitis. Intepretation of these findings is confounded by the fact that these studies were performed in the mouse, a species that is relatively resistant to uveitis. In this study, we utilized transgenic rats with constitutive expression of IFNgamma in the eye to investigate the effects of this cytokine in the induction, progression and susceptibility to uveitis in two well established models of uveitis; experimental autoimmune uveoretinitis (EAU) and endotoxin induced uveitis (EIU). The rats exhibit microphthalmia and microphakia but had no signs of cellular infiltration, indicating that secretion of IFNgamma in the eye does not result in the development of anterior or posterior uveitis. In contrast to the studies in mice, IFNgamma did not have a protective role in either EAU or EIU. On the contrary, EIU and EAU were exacerbated and an accelerated onset of EAU was observed in the transgenic rats. Analysis of the TCR repertoire of the retinas of transgenic and wild type rats with EAU at disease onset, revealed that the same T cell clonotypes were recruited into the retina suggesting that the effects of IFNgamma is at the level of the target tissues rather than at the level of lymphocyte priming. Taken together, our results suggest that local secretion of IFNgamma is not essential for initiation of uveitis and does not play an important role in down-regulation of the disease. On the contrary, IFNgamma contributes to disease susceptibility by promoting recruitment of inflammatory cells into the eye.
| Egwuagu, C E; Li, W; Yu, C-R et al. (2006) Interferon-gamma induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors. Oncogene 25:3670-9 |
| Takase, H; Yu, C-R; Liu, X et al. (2005) Induction of suppressors of cytokine signaling (SOCS) in the retina during experimental autoimmune uveitis (EAU): potential neuroprotective role of SOCS proteins. J Neuroimmunol 168:118-27 |
| Egwuagu, Charles E; Yu, Cheng-Rong; Li, Zhuqing et al. (2005) SOCS5 mRNA levels in peripheral blood mononuclear cells (PBMC): a potential bio-marker for monitoring response of uveitis patients to Daclizumab therapy. J Autoimmun 24:39-46 |
| Li, W; Nagineni, C N; Ge, H et al. (1999) Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens. J Biol Chem 274:9686-91 |
