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Interleukin-10 Upregulates Tumor Necrosis Factor Receptor Type-II (p75) Gene Expression in Endotoxin-Stimulated Human Monocytes
Harold L. Dickensheets,
Sherry L. Freeman,
Michael F. Smith Jr, and
Raymond P. Donnelly
From the Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD; and Department of Medicine, University of Virginia Health Sciences Center, Charlottesville, VA.
Interferon- (IFN-) upregulates expression of certain genes in monocytes, including cell-surface molecules such as HLA class II, B7, and ICAM-1. IFN- also potentiates production of cytokines such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1) and IL-12. Conversely, IL-10 downregulates expression of many of these same genes and often antagonizes the effects of IFN-. IL-10 is known to inhibit TNF- production in lipopolysaccharide (LPS)-stimulated monocytes; however, the effects of IL-10 on TNF receptor (TNF-R) expression are not well defined. We examined the effects of IL-10 on production of both membrane-associated (m) and soluble (s) TNF-R type II (sTNF-RII) by purified human CD14+ monocytes. We also compared the effects of IFN- and IL-10 on production of TNF- and sTNF-RII by these cells. Monocytes constitutively expressed low levels of TNF-RII mRNA and mTNF-RII protein. LPS stimulation induced rapid, but transient loss (shedding) of mTNF-RII molecules and a delayed, but marked increase in TNF-RII mRNA levels. IL-10 increased expression of both mTNF-RII and sTNF-RII by LPS-stimulated monocytes, whereas IFN- decreased their expression. The increased levels of sTNF-RII in cultures of IL-10-treated monocytes correlated directly with increased levels of TNF-RII mRNA and inversely with the levels of TNF- mRNA. The ability of IL-10 to upregulate TNF-RII gene expression was transcriptionally mediated because actinomycin D blocked this effect. Furthermore, IL-10 treatment did not alter the half-life of TNF-RII mRNA transcripts in LPS-stimulated monocytes. To further examine the mechanism by which IL-10 potentiates TNF-RII gene expression, a 1.8-kb fragment of the human TNF-RII promoter cloned into a luciferase expression vector (pGL2-basic) was transfected into the IL-10-responsive macrophage cell line, RAW264.7. Although IL-10 alone induced only minimal promoter activity in these cells, it markedly increased the LPS-induced response, providing further evidence that the ability of IL-10 to amplify TNF-RII gene expression is transcriptionally controlled. Together, these findings demonstrate that IL-10 coordinately downregulates expression of TNF- and upregulates expression of TNF-RII, particularly the soluble form of this receptor, in monocytes.
Blood, Vol. 90 No. 10 (November 15), 1997:
pp. 4162-4171
© 1997 by The American Society of Hematology.
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