The role of inflammation in the pathogenesis of dry eye disease

Purpose. The objective of this research was to understand the role of inflammation in dry eye disease. Four areas of study were pursued to achieve this goal: Part 1. To compare human β-defensin (hBD) expression in the conjunctival epithelium of moderately dry eye patients with normal patients and determine if proinflammatory cytokines or bacteria can modulate the expression of human β-defensins-1, 2 and 3 by human conjunctival epithelial cells (hCJEC) in culture. Part 2. To study the effect of exposure to interleukin-1 (IL-1) on cytokine gene expression by human corneal epithelial cells (HCEC) and hCJEC in culture. Part 3. To compare conjunctival epithelial cytokine expression in normal and moderate dry eye patients. Part 4. To compare cytokine and defensin expression in response to experimental dry eye (EDE) in an IL-1 Receptor-1 (IL-1R1) deficient (KO) mouse strain with age-matched wild type mice (WT).;Results. Part 1. hBD-2 was expressed in CIC samples of dry eye patients but not normal patients, while hBD-1 and hBD-3 were detected in all subjects. hBD-2 upregulation but no difference in the expression of hBD-1 and 3 was observed in hCJEC exposed to interleukin (IL)-1β, IL-1β + tumor necrosis factor-α, or heat-killed PA. hBD-2 protein secretion matched RT-PCR data. Part 2. IL-1 modulated several cytokines, chemokines, adhesion molecules and other cytokine-related genes in both P-HCEC and SV40-HCEC. Bayesian analysis of the SV40-HCEC data revealed that the expression of 15 genes were significantly (p < 0.05) differentially regulated. Part 3. There was no major difference in inflammatory cytokine mRNA expression between dry eye and normal patients. Low levels of IL-1β protein was detected in the tear fluid of 3 dry eye and 3 normal patients. IL-1β modulated cytokine expression in hCJEC in a manner similar to its effect on HCEC. Part 4. Differences in the expression of inflammatory cytokine and antimicrobial molecules were noted between WT and KO mice following dry eye induction.;Conclusions. It can be speculated that the hBD-2 upregulation observed in moderately dry eye subjects was mediated by proinflammatory cytokine activity, though no major difference in ocular surface cytokine expression was noted between the two groups of subjects. IL-1β does function as a major modulator of the ocular surface inflammatory response, which was confirmed by its modulation of cytokine expression in both HCEC and hCJEC. Though the low levels of IL-1β in tear fluid (part 3) questioned its role in moderate dry eye, the differences in cytokine and defensin expression observed in the in vivo investigation (part 4) with the IL-1-R1 deficient mice demonstrated that IL-1 does play a part in the pathophysiology of experimentally induced dry eye. In summary, the results of this study question the role for inflammation in the pathogenesis of moderate dry eye, while concurrently demonstrating the important regulatory aspects of IL-1 on ocular surface epithelia and inflammation. (Abstract shortened by UMI.).