Interleukin-10 Upregulates Tumor Necrosis Factor Receptor Type-II (p75) Gene Expression in Endotoxin-Stimulated Human Monocytes

• Published in: Blood Vol. 90; no. 10; pp. 4162 - 4171
• Main Authors: Dickensheets, Harold L., Freeman, Sherry L., Smith, Michael F., Donnelly, Raymond P.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-11-1997; The Americain Society of Hematology
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Cell Adhesion Molecules - biosynthesis; Cell Adhesion Molecules - genetics; Cells, Cultured; Endotoxins - pharmacology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - drug effects; Humans; Immunobiology; Interleukin-10 - pharmacology; Lymphokines, interleukins ( function, expression); Monocytes - drug effects; Monocytes - metabolism; Receptors, Tumor Necrosis Factor - biosynthesis; Receptors, Tumor Necrosis Factor - genetics; Regulatory factors and their cellular receptors; Human; Regulation(control); Monocyte; Cytokine; Interleukin 10; Stimulation; Gene expression; Tumor necrosis factor α; Biological receptor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V90.10.4162

Interferon-γ (IFN-γ) upregulates expression of certain genes in monocytes, including cell-surface molecules such as HLA class II, B7, and ICAM-1. IFN-γ also potentiates production of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-12. Conversely, IL-10 downregulates expression of many of these same genes and often antagonizes the effects of IFN-γ. IL-10 is known to inhibit TNF-α 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-γ and IL-10 on production of TNF-α 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-γ 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-α 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-α and upregulates expression of TNF-RII, particularly the soluble form of this receptor, in monocytes.