title: Induction of tumour necrosis factor receptor-expressing macrophages by interleukin-10 and macrophage colony-stimulating factor in rheumatoid arthritis.
abstract: Despite its potent ability to inhibit proinflammatory cytokine synthesis, interleukin (IL)-10 has a marginal clinical effect in rheumatoid arthritis (RA) patients. Recent evidence suggests that IL-10 induces monocyte/macrophage maturation in cooperation with macrophage-colony stimulating factor (M-CSF). In the present study, we found that the inducible subunit of the IL-10 receptor (IL-10R), type 1 IL-10R (IL-10R1), was expressed at higher levels on monocytes in RA than in healthy controls, in association with disease activity, while their expression of both type 1 and 2 tumour necrosis factor receptors (TNFR1/2) was not increased. The expression of IL-10R1 but not IL-10R2 was augmented on monocytes cultured in the presence of RA synovial tissue (ST) cell culture supernatants. Cell surface expression of TNFR1/2 expression on monocytes was induced by IL-10, and more efficiently in combination with M-CSF. Two-color immunofluorescence labeling of RA ST samples showed an intensive coexpression of IL-10R1, TNFR1/2, and M-CSF receptor in CD68+ lining macrophages. Adhered monocytes, after 3-day preincubation with IL-10 and M-CSF, could produce more IL-1beta and IL-6 in response to TNF-alpha in the presence of dibutyryl cAMP, as compared with the cells preincubated with or without IL-10 or M-CSF alone. Microarray analysis of gene expression revealed that IL-10 activated various genes essential for macrophage functions, including other members of the TNFR superfamily, receptors for chemokines and growth factors, Toll-like receptors, and TNFR-associated signaling molecules. These results suggest that IL-10 may contribute to the inflammatory process by facilitating monocyte differentiation into TNF-alpha-responsive macrophages in the presence of M-CSF in RA.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medicine, Dentistry, Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takasugi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Iwahashi
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Jiro
authors.initials: J
authors.lastname: Yamana
authors.forename: Katsue
authors.initials: K
authors.lastname: Sunahori
authors.forename: Masanori
authors.initials: M
authors.lastname: Kawashima
authors.forename: Masao
authors.initials: M
authors.lastname: Yamada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D002457:Cell Extracts / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004338:Drug Combinations; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053709:Interleukin-10 Receptor alpha Subunit / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000097:blood / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002457:Cell Extracts; D016207:Cytokines; D004338:Drug Combinations; D053709:Interleukin-10 Receptor alpha Subunit; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor