title: Thrombin regulates chemokine induction during human retinal pigment epithelial cell/monocyte interaction.
abstract: 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-alpha (TNF-alpha) antibody, but not by anti-IL-1beta antibody. TNF-alpha 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-1beta- and TNF-alpha-induced chemokine production by HRPE cells, monocytes, and co-cultures. Interferon-gamma 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-alpha induction, suggesting important mechanisms for ocular inflammation during blood-retina barrier breakdown and intra-ocular hemorrhage.
authors.affiliation: Department of Ophthalmology, University of Michigan, Ann Arbor, Michigan 48105, USA.
authors.forename: A
authors.initials: A
authors.lastname: Yoshida
authors.forename: S G
authors.initials: SG
authors.lastname: Elner
authors.forename: Z M
authors.initials: ZM
authors.lastname: Bian
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: N W
authors.initials: NW
authors.lastname: Lukacs
authors.forename: V M
authors.initials: VM
authors.lastname: Elner
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D002450:Cell Communication / Q000502:physiology*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D018920:Coculture Techniques; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000502:physiology*; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000502:physiology*; D011994:Recombinant Proteins; D013917:Thrombin / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology
chemical_list: D000906:Antibodies; D018932:Chemokine CCL2; D018925:Chemokines; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013917:Thrombin