ABSTRACT
Transforming growth factor (TGF)-beta1 is expressed abundantly in the rheumatoid synovium. In this study, the inflammatory effect of TGF-beta1 in rheumatoid arthritis (RA) was investigated using cultured fibroblast-like synoviocytes (FLS) from RA and osteoarthritis (OA) patients, as well as non-arthritic individuals. mRNA expressions of IL-1beta, tumour necrosis factor (TNF)-alpha, IL-8, macrophage inflammatory protein (MIP)-1alpha and metalloproteinase (MMP)-1 were increased in RA and OA FLS by TGF-beta1 treatment, but not in non-arthritic FLS. Enhanced protein expression of IL-1beta, IL-8 and MMP-1 was also observed in RA FLS. Moreover, TGF-beta1 showed a synergistic effect in increasing protein expression of IL-1beta and matrix metalloproteinase (MMP)-1 with TNFalpha and IL-1beta, respectively. Biological activity of IL-1 determined by mouse thymocyte proliferation assay was also enhanced by 50% in response to TGF-beta1 in the culture supernatant of RA FLS. DNA binding activities of nuclear factor (NF)-kappaB and activator protein (AP)-1 were shown to increase by TGF-beta1 as well. These results suggest that TGF-beta1 contributes for the progression of inflammation and joint destruction in RA, and this effect is specific for the arthritic synovial fibroblasts.
Subject(s)
Arthritis, Rheumatoid/immunology , Cytokines/biosynthesis , Fibroblasts/immunology , Matrix Metalloproteinase 1/biosynthesis , Synovial Membrane/immunology , Transforming Growth Factor beta/pharmacology , Arthritis, Rheumatoid/enzymology , Cells, Cultured , Chemokine CCL3 , Chemokine CCL4 , Cytokines/genetics , Fibroblasts/drug effects , Fibroblasts/enzymology , Humans , Interleukin-1/biosynthesis , Interleukin-1/genetics , Interleukin-8/biosynthesis , Interleukin-8/genetics , Macrophage Inflammatory Proteins/biosynthesis , Macrophage Inflammatory Proteins/genetics , Matrix Metalloproteinase 1/genetics , NF-kappa B/metabolism , Osteoarthritis/immunology , RNA, Messenger/biosynthesis , Synovial Membrane/cytology , Synovial Membrane/enzymology , Transcription Factor AP-1/metabolism , Transcriptional Activation , Transforming Growth Factor beta1 , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/geneticsABSTRACT
This study was performed to investigate whether peroxisome proliterator-activated receptor-gamma (PPAR-gamma) exerted an anti-inflammatory effect on rheumatoid synovial cells and inhibited dysregulated proliferation. The expression of PPAR-gamma mRNA in cultured human synoviocytes and THP-1 cells was analysed by RT-PCR. PPAR-gamma was expressed in normal, osteoarthritis (OA), rheumatoid arthritis (RA) synovial cells as well as a human monocytic cell line, THP-1. In RA and OA synoviocytes, the induction of inflammatory cytokine mRNA expression such as TNF-alpha and IL-1beta was significantly inhibited by the natural PPAR-gamma agonist, 15 deoxy-Delta(12,14)prostaglandin J(2)(15d-PGJ(2)). The effect of PPAR-gamma on the nuclear factor (NF)-kappaB activity was tested by electrophoretic mobility shift assay (EMSA). Both troglitazone and 15d-PGJ(2)markedly inhibited TNF-alpha-induced NF-kappaB activation at 30 microM. However, PPAR-gamma agonist neither reduced proliferation nor induced apoptosis in RA synoviocytes when measured by XTT assay and fluorescence activated cell sorter (FACS) analysis. In contrast, it induced apoptosis in a dose-dependent manner in THP-1 cells and augmented TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well. In conclusion, these data demonstrate that PPAR-gamma is expressed in human synoviocytes and THP-1 cells, and the PPAR-gamma activation inhibits expression of inflammatory cytokines in RA synoviocytes. Furthermore, PPAR-gamma activation induces apoptosis by itself and augments TRAIL/Apo2L-induced apoptosis in THP-1 cells. These results suggest that PPAR-gamma agonists may provide a new therapeutic approach for RA.
Subject(s)
Apoptosis/immunology , Arthritis, Rheumatoid/immunology , Cytokines/biosynthesis , Fibroblasts/immunology , Microbodies/metabolism , Monocytes/immunology , Receptors, Cytoplasmic and Nuclear/physiology , Synovial Membrane/immunology , Transcription Factors/physiology , Apoptosis Regulatory Proteins , Arthritis, Rheumatoid/pathology , Cells, Cultured , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Interleukin-1/biosynthesis , Interleukin-1/metabolism , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Microbodies/immunology , Monocytes/metabolism , Monocytes/pathology , NF-kappa B/metabolism , Osteoarthritis/immunology , Osteoarthritis/pathology , RNA, Messenger/biosynthesis , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Cytoplasmic and Nuclear/genetics , Synovial Membrane/metabolism , Synovial Membrane/pathology , TNF-Related Apoptosis-Inducing Ligand , Transcription Factors/biosynthesis , Transcription Factors/genetics , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolism , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
From March 1982 to December 1992, 30 cases of thumb reconstruction with a free neurovascular wrap-around flap from the big toe were performed at Korea University Hospital. Twenty-nine of a total of 30 cases were successful and obtained excellent functional and cosmetic results. Postoperative complications included 1 case of graft failure, 6 partial skin necroses, 1 malunion, and 15 cases of resorption of iliac bone graft including 1 case of fatigue fracture of grafted bone. Even for the first metacarpal neck amputations, thumb reconstruction with a free neurovascular wrap-around flap was possible; however, limitation of motion of the reconstructed thumb and resorption of the grafted bone occurred. Thumb reconstruction with a wrap-around free flap from the big toe gives excellent cosmetic and functional results and causes minimal morbidity on the donor site.
