INTERLEUKIN-6 (IL-6) GENE-EXPRESSION AND SECRETION BY CYTOKINE-STIMULATED HUMAN RETINAL-PIGMENT EPITHELIAL-CELLS

Retinal and choroidal inflammatory lesions are important causes of visual loss, but the mechanisms regulating intraocular inflammation remain poorly understood. By virtue of its position at the blood-retina barrier, the retinal pigment epithelium (RPE) cells may be critical to the initiation and propagation of ocular inflammation. Previously we showed that cytokine-stimulated RPE cells produce interleukin-8, a well-defined chemotactic factor for neutrophils and lymphocytes. In this study, we found that human RPE cells stimulated by human recombinant interleukin-1-β (rIL-1β) or tumor necrosis factor-α (rTNF-α) produce interleukin-6 (IL-6). Using a plasmacytoma proliferation assay, significant levels of IL-6 were found in media of RPE cells stimulated with either rIL-1β or rTNF-α for 4 hr. Progressive accumulation of IL-6 in media overlying stimulated RPE cells occurred over the subsequent 20 hr. IL-1β was a significantly more potent stimulator of RPE IL-6 production than TNF-α. RPE IL-6 production in response to each of these cytokines was also dose-dependent over a range of 20 pg to 20 ng ml-1. Specific anti IL-6 antibody, but not control immunoglobulin, neutralized RPE-derived IL-6 activity in the plasmacytoma proliferation assays. RPE IL-6 mRNA levels were detectable 1 hr after cytokine stimulation, plateaued within 8 hr in 24-hr assays, and demonstrated dose-dependent kinetics in 6 hr assays. Lipopolysaccharide failed to induce RPE IL-6 mRNA expression or RPE IL-6 production. Our findings indicate that RPE cells express IL-6 mRNA and secrete biologically active IL-6 when stimulated by inflammatory cytokines. RPE IL-6 secretion may be important in ocular lesions involving differentiation and activation of lymphocytes. © 1992.