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J. Biol. Chem., Vol. 279, Issue 31, 32325-32332, July 30, 2004

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FGF-2 Induced by Interleukin-1 through the Action of Phosphatidylinositol 3-Kinase Mediates Endothelial Mesenchymal Transformation in Corneal Endothelial Cells^*

Hyung Taek Lee, Jeong Goo Lee, Moonseok Na, and EunDuck P. Kay¶

From the Doheny Eye Institute and Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033

Our previous work demonstrated that both polymorphonuclear leukocytes (PMNs) and protein fractions released from PMNs induced de novo synthesis of fibroblast growth factor 2 (FGF-2), which in turn becomes the direct mediator of endothelial mesenchymal transformation observed in corneal endothelial cells (CECs). To identify the protein factor, we used ProteinChip Array technology. Protein fractions obtained from the conditioned medium released by PMNs were resolved by two-dimensional electrophoresis with immobilized pH gradient strips. Most of the protein spots, with molecular masses of 17 kDa, were sequentially subjected to in-gel trypsin digestion and mass spectrometry. The 17-kDa peptide band was identified as interleukin-1 (IL-1). Biological activities of IL-1 were further determined; IL-1 altered the shape of CECs from polygonal to fibroblastic morphologies in a time- and dose-dependent manner, whereas neutralizing IL-1 antibody, neutralizing antibody to FGF-2, and LY294002 blocked the action of IL-1. IL-1 greatly increased the levels of FGF-2 mRNA in a time- and dose-dependent manner; IL-1 stimulated expression of all isoforms of FGF-2. IL-1 initially induced nuclear accumulation of FGF-2 and facilitated translocation of FGF-2 to plasma membrane and extracellular matrix. IL-1 activated phosphatidylinositol (PI) 3-kinase, the enzyme activity of which was greatly stimulated after a 5-min exposure to IL-1. This early and rapid activation of PI 3-kinase greatly enhanced FGF-2 production in CECs; pretreatment with LY294002 hampered the induction activity of IL-1. These observations suggest that IL-1 takes part in endothelial to mesenchymal transformation of CECs through its inductive potential on FGF-2 via the action of PI 3-kinase.

Received for publication, May 10, 2004 , and in revised form, May 27, 2004.

^* This work was supported in part by NEI, National Institutes of Health Grants EY06431 and EY03040 and a grant from Research to Prevent Blindness, New York. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence may be addressed: Doheny Eye Institute, 1450 San Pablo St., DVRC 203, Los Angeles, CA 90033. Tel.: 323-442-6625; Fax: 323-442-6688; E-mail: ekay{at}usc.edu.

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