Cunha, Andre, Zhang, Qin, Prentiss, Melissa, Wu, Xiaoqiu, Kainz, Vanessa, Xu, Yongyao, Vrouvlianis, Joanna, Li, Hui, Rangaswamy, Nalini, Leehy, Barrett, Mcgee, Terri, Bell, Christie, Bigelow, Chad, Kansara, Viralbhai, 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