Tumor Necrosis Factor α and Interleukin-1α Stimulate Late Shedding of p75 TNF Receptors but Not p55 TNF Receptors from Human Monocytes

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Abstract
Soluble receptors for TNF (sTNF-R) are present at elevated concentrations in the synovial fluid of patients with rheumatoid arthritis. They are presumably released by cells of the synovial membrane, including the monocyte-derived synovial macrophages. Cytokines from the synovium, including IL-1 and TNF-α, may stimulate release. We therefore examined the release of sTNF-R from monocytes exposed to IL-1 and TNF-α. Elutriator-purified human blood monocytes spontaneously released both the p75 and the p55 sTNF-R (1011 ± 199 and 177 ± 20 pg/106 cells, respectively, mean ± SEM) during 48 h of in vitro culture. TNF-α and IL-1α induced time- and concentration-dependent increases in the release of sTNF-R75 from monocytes, but neither had a measurable effect on the release of sTNF-R55. The release of sTNF-R75 was inhibited by cycloheximide. Neither lymphocytes nor polymorphonuclear leukocytes (PMN) released measurable sTNF-R spontaneously or in response to stimulation with IL-1α, but TNF-α stimulated the release of small amounts of sTNF-R75 by PMN. The timing, cycloheximide sensitivity, and selectivity of stimulated release of TNF-R75 by monocytes are consistent with previous observations on other cell types of late (8-20 h) increased synthesis and turnover of cell surface TNF-R75, but not TNF-R55, after stimulation with TNF-α or IL-1. These observations help to explain why elevated levels of sTNF-R in synovial fluid coexist with enhanced expression of cell surface TNF-R on synovial macrophages in rheumatoid arthritis.