INTERLEUKIN-7 (IL-7) INDUCES RETINAL-PIGMENT EPITHELIAL-CELL MCP-1 AND IL-8

The neuroectodermally-derived retinal pigment epithelium (RPE) forms p art of the blood-retina barrier where it is strategically-positioned t o regulate leukocyte infiltration in retinal diseases. Activated human RPE cells possess several functions enabling them to perform this rol e including expression of HLA-DR antigens, production of intercellular adhesion molecule-1, and secretion of monocyte chemotactic protein-1 and interleukin-8. In this study, we examined the ability of interleuk in-7 to induce RPE-derived monocyte chemotactic protein-1 and interleu kin-8 and assessed the potentiating effects of interleukin-7 on interl eukin-1 beta- and tumor necrosis factor-alpha-induced RPE monocyte che motactic protein-1 and interleukin-8 production. Human RPE cells incub ated with interleukin-7 (1-100 ng ml(-1)) for 24 hr secreted significa nt levels of antigenic RPE monocyte chemotactic protein-1 and interleu kin-8 in a dose-dependent fashion interleukin-7 (P < 0.05). RPE costim ulation with interleukin-7 and interleukin-1 beta (2 ng ml(-1)) or tum or necrosis factor-alpha (2 ng ml(-1)) resulted in additive increases (P < 0.05) in secreted monocyte chemotactic protein-1 and interleukin- 8. Steady-state RPE monocyte chemotactic protein-1 mRNA was substantia lly increased by interleukin-7 (1-100 ng ml(-1)), while RPE interleuki n-8 mRNA was mildly elevated by higher doses of interleukin-7 (10-100 ng ml(-1)). Time-dependent increases in RPE monocyte chemotactic prote in-1 and interleukin-8 mRNA were noted. RPE monocyte chemotactic prote in-1 mRNA peaked at 2 hr and decreased over 8 hr and 24 hr. Whereas, R PE interleukin-8 mRNA was perceptible at 2 hr, maximal at 8 hr, and re duced by 24 hr. Interleukin-7 potentiated interleukin-1 beta-induced m onocyte chemotactic protein-1 and interleukin-8 steady-state mRNA expr ession at all interleukin-7 concentrations. Interleukin-7 potentiated tumor necrosis factor-alpha-induced RPE monocyte chemotactic protein-1 steady-state mRNA expression at all doses of interleukin-7 while only high dose interleukin-7 (100 ng ml(-1)) enhanced tumor necrosis facto r-alpha-induced RPE interleukin-8 steady-state gene expression. Our da ta show that interleukin-7 is a primary stimulus of RPE monocyte chemo tactic protein-1 and interleukin-8. This is one of the first reports d emonstrating: (1) interleukin-7 induction of monocyte chemotactic prot ein-1 in any cell type, and (2) interleukin-7 induction of interleukin -8 in resident, tissue-based cells. These studies suggest that interle ukin-7 potentiation of interleukin-1 beta and tumor necrosis factor-al pha-induced RPE monocyte chemotactic protein-1 and IL-8 may be importa nt for the elicitation of leukocyte chemotaxins in diseased retinal ti ssue when only low ambient levels of individual pro-inflammatory cytok ines are present. (C) 1996 Academic Press Limited