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(American Journal of Pathology. 2001;159:1171-1180.)
© 2001 American Society for Investigative Pathology

Regular Articles

Thrombin Regulates Chemokine Induction during Human Retinal Pigment Epithelial Cell/Monocyte Interaction

Ayako Yoshida^*, Susan G. Elner^*, Zong-Mei Bian^*, Steven L. Kunkel, Nicholas W. Lukacs and Victor M. Elner^*

From the Department of Ophthalmology,^*
W. K. Kellogg Eye Center, and the Department of Pathology,
University of Michigan, Ann Arbor, Michigan

Thrombin, an important clotting factor, extravasates at sites of blood-retina barrier breakdown that is often associated with many retinal diseases. Here we investigated the effects of thrombin on human retinal pigment epithelial (HRPE) cells, monocytes, and HRPE cell/monocyte co-cultures. Thrombin induced secretion and mRNA expression of HRPE interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1). Thrombin also enhanced IL-8 and MCP-1 by HRPE cell/monocyte co-cultures, by apparently enhancing cell-cell contact mechanisms. The thrombin effects on IL-6 secretion were similar to those on chemokine secretion. Thrombin-induced chemokines by co-cultures were inhibited by anti-tumor necrosis factor- (TNF-) antibody, but not by anti-IL-1ß antibody. TNF- was detected in cell lysates of monocytes detached from HRPE cells after co-culture stimulation with thrombin. HRPE cells mainly produced these chemokines. However, thrombin generally potentiated exogenous IL-1ß- and TNF--induced chemokine production by HRPE cells, monocytes, and co-cultures. Interferon- potentiated chemokine secretion by co-cultures with or without thrombin. Our results indicate that thrombin may cause leukocyte recruitment by inducing HRPE cell and monocyte chemokine and by enhancing HRPE cell/monocyte interactions, in part because of monocyte TNF- induction, suggesting important mechanisms for ocular inflammation during blood-retina barrier breakdown and intra-ocular hemorrhage.

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