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Published online before print April 17, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0108076

Received for publication January 30, 2008.
Revised February 21, 2008.
Accepted for publication February 22, 2008.

Article

Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide

Yan Sun ^*, Todd Fox , Gautam Adhikary ^*, Mark Kester , and Eric Pearlman ^*@

*Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA; and Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania, USA

^@ To whom correspondence should be addressed. E-mail: eric.pearlman{at}case.edu.

	Abstract

Ceramide is recognized as an antiproliferative and proapoptotic sphingolipid metabolite; however, the role of ceramide in inflammation is not well understood. To determine the role of C6-ceramide in regulating inflammatory responses, human corneal epithelial cells were treated with C6-ceramide in 80 nm diameter nanoliposome bilayer formulation (Lip-C6) prior to stimulation with UV-killed Staphylococcus aureus. Lip-C6 (5 µM) inhibited the phosphorylation of proinflammatory and proapoptotic MAP kinases JNK and p38 and production of neutrophil chemotactic cytokines CXCL1, CXCL5, and CXCL8. Lip-C6 also blocked CXC chemokine production by human and murine neutrophils. To determine the effect of Lip-C6 in vivo, a murine model of corneal inflammation was used in which LPS or S. aureus added to the abraded corneal surface induces neutrophil infiltration to the corneal stroma, resulting in increased corneal haze. Mice were treated topically with 2 nMoles (811 ng) Lip-C6 or with control liposomes prior to, or following, LPS or S. aureus stimulation. We found that corneal inflammation was significantly inhibited by Lip-C6 but not control liposomes given prior to, or following, activation by LPS or S. aureus. Furthermore, Lip-C6 did not induce apoptosis of corneal epithelial cells in vitro or in vivo, nor did it inhibit corneal wound healing. Together, these findings demonstrate a novel, anti-inflammatory, nontoxic, therapeutic role for liposomally delivered short-chain ceramide.

Key Words: ceramide • nanoparticles • liposomes • cornea • chemokines