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The hierarchy of pro-inflammatory cytokines in ocular inflammation

Cunha, Andre and Zhang, Qin and Prentiss, Melissa and Wu, Xiaoqiu and Kainz, Vanessa and Xu, Yongyao and Vrouvlianis, Joanna and Li, Hui and Rangaswamy, Nalini and Leehy, Barrett and Mcgee, Terri and Bell, Christie and Bigelow, Chad and Kansara, Viralbhai and Huang, Qian and Wu, Henry (2017) The hierarchy of pro-inflammatory cytokines in ocular inflammation. Current eye research. pp. 1-13. ISSN 1460-2202

Abstract

Purpose: The concept of tissue dependent cytokine hierarchy has been demonstrated in a number of diseases but it has not been investigated in ophthalmic diseases. Here we evaluated the functional hierarchy of IL-1, IL-6, IL-17A and TNF in the induction of ocular inflammation.
Materials and Methods: We delivered AAV vectors expressing IL-1β, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer. We also used an in vitro human system to test the effect of cytokines on barrier function.
Results: We found that IL-1 had the highest ability to initiate ocular inflammation. The continuous overexpression of IL-1 resulted in a significant upregulation of additional pro-inflammatory mediators in the eye. Using SLO and OCT imaging techniques we showed that a low dose of AAVIL-1β was sufficient and was as pathogenic as a high dose of TNF in inducing vascular leakage, retinal degeneration and cellular infiltration. Furthermore, only a marginal increase in IL-1 was enough to cause cellular infiltration thus confirming the highly pathogenic nature of IL-1 in the eye. Contrary to our expectation, IL-6 or IL-17A had minimal or no effect in the eye. To examine the clinical relevance of our findings we used an impedance assay to show that IL-1β alone or TNF alone was able to cause primary human retinal endothelial cell barrier dysfunction in vitro. Again, IL-6 alone or IL-17A alone had no effect on barrier function however, in the presence of IL-1 or TNF, IL-17A but not IL-6 may provide additive pro-inflammatory effects.
Conclusions: Our studies demonstrate the existence of a functional hierarchy of pro-inflammatory cytokines in the eye and we show that IL-1 is the most pathogenic when it is continuously expressed in the eye.

Item Type: Article
Keywords: Cytokines, AAV, ocular inflammation
Date Deposited: 26 Dec 2017 00:45
Last Modified: 26 Dec 2017 00:45
URI: https://oak.novartis.com/id/eprint/34889

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