title: Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10.
abstract: By regulating monocyte and macrophage production of IL-1, its receptor, and its receptor antagonist, IL-4 and IL-10 may exert significant anti-inflammatory activity. We determined whether a similar multicomponent process controlling TNF activity was regulated by IL-4 and IL-10 in nonadherent monocytes and synovial fluid macrophages. Previous studies differed in their conclusions. For both the p75 and p55 TNF receptors, mRNA levels, surface receptor expression, and soluble receptor levels were measured for blood monocytes incubated in vitro for 17, 40, or 64 h with IL-4 or IL-10. The predominant TNF receptor on monocytes, the p75 receptor, was down-regulated by IL-4 at the mRNA level. In turn, both surface and soluble receptor levels on LPS-stimulated cells were reduced and the inhibitory effects were maintained for at least 64 h. In contrast, IL-10 increased surface and soluble p75 TNF receptor levels on monocytes for approximately 40 h, which reflected an increase in receptor mRNA. These studies suggest that IL-4 and IL-10 do not directly regulate the cleavage of TNF receptors from monocytes and macrophages. Addition of an Ab to IL-10 suggested that the stimulatory effects of LPS on p75 TNF receptor expression were due, at least in part, to LPS stimulation of IL-10 production and that IL-4 acted, in part, by decreasing IL-10 production. IL-4 was down-regulatory and IL-10 stimulatory for TNF receptor expression by synovial fluid macrophages. By increasing surface receptor levels, IL-10 enhanced the activities of TNF on monocytes for IL-1beta production. By increasing soluble TNF receptor levels, IL-10 may limit only temporarily the activity of other TNF-responsive cells. This study questions the benefit of IL-10 to resolving TNF-associated inflammation.
authors.affiliation: Department of Microbiology and Infectious Diseases, School of Medicine, Flinders University of South Australia, Adelaide.
authors.forename: P H
authors.initials: PH
authors.lastname: Hart
authors.forename: E K
authors.initials: EK
authors.lastname: Hunt
authors.forename: C S
authors.initials: CS
authors.lastname: Bonder
authors.forename: C J
authors.initials: CJ
authors.lastname: Watson
authors.forename: J J
authors.initials: JJ
authors.lastname: Finlay-Jones
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology; D001483:Base Sequence; D002462:Cell Membrane / Q000276:immunology; D015342:DNA Probes / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D012995:Solubility; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015342:DNA Probes; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D016753:Interleukin-10; D015847:Interleukin-4