title: Differential expression, function and response to inflammatory stimuli of 11beta-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation.
abstract: Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation. We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Expression, activity and function of 11beta-HSD1 was assessed in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid arthritis or osteoarthritis. 11beta-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis factor-alpha or IL-1beta (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold; synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-gamma was without effect, and there was no difference in 11beta-HSD1 expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the presence of 100 nmol/l cortisone, IL-6 production--a characteristic feature of synovial derived fibroblasts--was significantly reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11beta-HSD inhibitor, emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences in fibroblast-derived glucocorticoid production (via the enzyme 11beta-HSD1) between cells from distinct anatomical locations may play a key role in the predeliction of certain tissues to develop persistent inflammation.
authors.affiliation: Division of Medical Sciences, Institute of Biomedical Research, The University of Birmingham Medical School, Birmingham, UK.
authors.forename: Rowan S
authors.initials: RS
authors.lastname: Hardy
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cooper
authors.forename: Greg
authors.initials: G
authors.lastname: Parsonage
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.forename: Debbie L
authors.initials: DL
authors.lastname: Hardie
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000378:metabolism; D001853:Bone Marrow / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003348:Cortisone / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology*; D005938:Glucocorticoids / Q000096:biosynthesis; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D010003:Osteoarthritis / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000093242:Interleukin-6 Inhibitors
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone; D005938:Glucocorticoids; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors