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1 From the Ocular Surface and Tear Center, Bascom Palmer Eye Institute, Department of Ophthalmology; and 2 Department of Urology, University of Miami School of Medicine, Florida.
PURPOSE. To evaluate the effect of doxycycline on the regulation of interleukin (IL)-1 expression and activity in human cultured corneal epithelium.
METHODS. Human corneal limbal epithelium (HLE) was cultured from explants
prepared from limbal rings of donor corneas. Primary cultured limbal
epithelial cells were treated with either 10 µg/ml lipopolysaccharide
(LPS), LPS with 10 µg/ml doxycycline, or LPS with 0.1 mg/ml
methylprednisolone (MP) for 24 hours. The intracellular and supernatant
protein amounts of IL-1
, the precursor and mature forms of IL-1ß,
IL-1 receptor antagonist (IL-1 RA), and the intracellular level of
IL-1ß–converting enzyme (ICE) were measured with enzyme-linked
immunosorbent assays (ELISAs). Western blot analysis was performed to
evaluate IL-1 RA protein. mRNA steady state amounts were determined by
RNase protection assay (RPA) for IL-1, IL-1ß, IL-1 RA, and ICE.
RESULTS. LPS increased the mRNA and protein amounts of intracellular and
released IL-1, mature IL-1ß, and IL-1 RA. Doxycycline inhibited
the LPS-induced IL-1ß increase in the mRNA and protein amounts in the
corneal epithelium and upregulated the expression of the
anti-inflammatory IL-1 RA protein. In addition, doxycycline reduced the
steady state level of the cellular ICE protein but did not affect the
level of ICE transcripts. IL-1ß secreted to the conditioned media of
HLE was functionally active in inducing matrix metalloproteinase
(MMP)-1 and MMP-3 in cultured corneal fibroblasts. Doxycycline
significantly decreased IL-1ß bioactivity in the supernatants from
LPS-treated corneal epithelial cultures. These effects were comparable
to those induced by the corticosteroid, MP.
CONCLUSIONS. Doxycycline can suppress the steady state amounts of mRNA and protein of IL-ß and decrease the bioactivity of this major inflammatory cytokine. These data may partially explain the clinically observed anti-inflammatory properties of doxycycline. The observation that doxycycline was equally potent as a corticosteroid, combined with the relative absence of adverse effects, makes it a potent drug for a wide spectrum of ocular surface inflammatory diseases.
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