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(Investigative Ophthalmology and Visual Science. 2006;47:2369-2380.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1649
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Multifunctional Roles of Human Cathelicidin (LL-37) at the Ocular Surface

Ling C. Huang, Tihomira D. Petkova, Rose Y. Reins, Rita J. Proske, and Alison M. McDermott

From the University of Houston, College of Optometry, Houston, Texas.

PURPOSE. The goals of this study were to examine the expression of the antimicrobial peptide LL-37 in the corneal epithelium during wound healing and to investigate whether LL-37 stimulates human corneal epithelial cell (HCEC) migration, proliferation, and cytokine production.

METHODS. Expression of LL-37 was determined by RT-PCR and immunostaining in tissue sections and HCECs scraped from corneas before (original) and after (regrown) re-epithelialization. The antimicrobial activity of LL-37 against Pseudomonas aeruginosa (PA) was determined in the presence of NaCl and tears. Blind-well chamber assays were performed to study the effect of LL-37 on migration. Proliferation was determined using calcein-AM, and cytotoxicity was evaluated by MTT assay. ELISA was performed to assess the ability of LL-37 to stimulate HCEC cytokine secretion.

RESULTS. LL-37 peptide was present throughout the corneal epithelium (n = 4). All original corneal epithelial samples expressed a low level of LL-37 (n = 10). Regrown epithelial samples collected 24 (n = 3 of 5) or 48 (n = 4 of 5) hours after wounding showed upregulated expression of LL-37. LL-37 killed PA in the presence of NaCl (EC50= 10.3 ± 2.5 µg/mL) and retained its activity in tears (n = 3). LL-37 induced HCEC migration (n = 5) and secretion of IL-8, IL-6, IL-1ß, and TNF-{alpha} (2- to 23-fold, n = 4–7). Inhibitor studies indicated that LL-37’s effects are mediated through multiple pathways involving a G protein-coupled receptor (formyl peptide receptor–like 1 in migration) and the epidermal growth factor receptor (n = 2 to 5). LL-37 did not stimulate HCEC proliferation (n = 3) and high concentrations (>10 µg/mL) were cytotoxic (n = 3).

CONCLUSIONS. LL-37 expression is upregulated in regenerating human corneal epithelium, has antibacterial activity against ocular pathogens under physiologically relevant conditions, and stimulates HCEC migration and cytokine production. These findings suggest that LL-37 acts as a multifunctional mediator that helps protect the cornea from infection and modulates wound healing.




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