Neutralization of ocular surface TNF-α reduces ocular surface and lacrimal gland inflammation induced by in vivo dry eye.
OBJECTIVE
The purpose of this study was to investigate the effectiveness of tumor necrosis factor (TNF)-α blocker for treatment of dry eye (DE)-induced inflammation and determine a more effective method to suppress lacrimal gland inflammation. Efficacy of topical versus systemic administration of TNF-α blockers was determined using a murine dry eye (DE) model.


METHODS
The TNF-α blocker HL036 was developed by modification of the TNF receptor I. Protein purity, binding affinity, and clearance of TNF-α was compared with etanercept. Using DE-induced C57BL/6 mice, corneal erosion and goblet cell counts were measured after subcutaneous or topical treatment with etanercept or HL036. Inflammatory cytokines in cornea and lacrimal glands were determined by quantitative RT-PCR and ELISA.


RESULTS
HL036 showed TNF-α binding affinity comparable to etanercept, as measured by surface plasmon resonance. HL036 concentration was significantly higher in cornea and anterior segment than etanercept and effectively eliminated TNF-α on ocular surfaces. Etanercept was preferentially concentrated in the posterior segment. Corneal erosion and goblet cell counts were improved only with topically applied etanercept and HL036. Ocular surface IFN-γ, IL-6, and IL-21 were significantly decreased by topical HL036. DE-induced lacrimal gland IFN-γ and IL-6 expression was effectively suppressed by topical etanercept and HL036.


CONCLUSIONS
Topical TNF-α blockers effectively suppressed lacrimal gland and corneal inflammation by suppressing IFN-γ, IL-21, and IL-6. Differences in TNF-α affinity, clearance, and local concentration of blockers may account for the anti-inflammatory effects in different ocular regions.
Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.
Yong Woo
YW
Ji
Yu Jeong
YJ
Byun
Wungrak
W
Choi
Eunae
E
Jeong
Jin Sun
JS
Kim
Haemi
H
Noh
Eun Sun
ES
Kim
Yun Jung
YJ
Song
Seung Kook
SK
Park
Hyung Keun
HK
Lee
D000818:Animals; D002452:Cell Count; D003315:Cornea / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003607:Dacryocystitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D020397:Goblet Cells / Q000473:pathology; D007074:Immunoglobulin G / Q000494:pharmacology; D007634:Keratitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007638:Keratoconjunctivitis Sicca / Q000150:complications*; D007765:Lacrimal Apparatus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
cytokines; dry eye; lacrimal gland; tumor necrosis factor‐α