OBJECTIVE: Dendritic cells (DCs) are enriched in RA synovium and have been implicated in the pathogenesis of RA primarily through their ability to present autoantigen and activate T cells. However, whether DCs play an effector role in cartilage destruction is unknown. The aim of this study was to investigate whether DCs can induce collagen release from cartilage and the mechanism involved. METHODS: Human monocyte-derived DCs (mDCs) were activated with CD40 ligand (CD40L) to mimic DC-T-cell interaction, and supernatants were incubated with cartilage explants. Hydroxyproline was assessed as a measure of collagen release and collagenolytic activity was measured by a bioassay using tritiated collagen. TNF-alpha in DC supernatants was measured by specific ELISA. RESULTS: Supernatants from CD40L-activated mDCs, but not unstimulated mDCs, strongly induced the destruction of cartilage collagen. mDC supernatants did not contain collagenases but did induce collagenolytic activity in cartilage explants. Neutralization of TNF-alpha in mDC supernatants completely abolished collagenolysis. CONCLUSIONS: This study shows that mDCs, upon CD40-ligation, induce cartilage collagen degradation through an indirect mechanism via the production of TNF-alpha. Our data suggest a potential important role for mDC-derived TNF-alpha in RA, which is in line with the previously reported observations that DCs are a major source of TNF-alpha in early autoimmune lesions and that anti-TNF-alpha therapeutics effectively suppress joint damage in RA patients. We propose that DCs can act as effectors in cartilage destruction, adding a new aspect to the functional role of DCs in RA pathogenesis.
OBJECTIVE: Dendritic cells (DCs) are enriched in RA synovium and have been implicated in the pathogenesis of RA primarily through their ability to present autoantigen and activate T cells. However, whether DCs play an effector role in cartilage destruction is unknown. The aim of this study was to investigate whether DCs can induce collagen release from cartilage and the mechanism involved. METHODS:Human monocyte-derived DCs (mDCs) were activated with CD40 ligand (CD40L) to mimic DC-T-cell interaction, and supernatants were incubated with cartilage explants. Hydroxyproline was assessed as a measure of collagen release and collagenolytic activity was measured by a bioassay using tritiated collagen. TNF-alpha in DC supernatants was measured by specific ELISA. RESULTS: Supernatants from CD40L-activated mDCs, but not unstimulated mDCs, strongly induced the destruction of cartilage collagen. mDC supernatants did not contain collagenases but did induce collagenolytic activity in cartilage explants. Neutralization of TNF-alpha in mDC supernatants completely abolished collagenolysis. CONCLUSIONS: This study shows that mDCs, upon CD40-ligation, induce cartilage collagen degradation through an indirect mechanism via the production of TNF-alpha. Our data suggest a potential important role for mDC-derived TNF-alpha in RA, which is in line with the previously reported observations that DCs are a major source of TNF-alpha in early autoimmune lesions and that anti-TNF-alpha therapeutics effectively suppress joint damage in RA patients. We propose that DCs can act as effectors in cartilage destruction, adding a new aspect to the functional role of DCs in RA pathogenesis.
Authors: Denise E De Almeida; Song Ling; Xiujun Pi; Anne M Hartmann-Scruggs; Paul Pumpens; Joseph Holoshitz Journal: J Immunol Date: 2010-06-30 Impact factor: 5.422
Authors: Mikhail Y Kochukov; Terry A McNearney; Huaizhi Yin; Liping Zhang; Fei Ma; Larissa Ponomareva; Sarah Abshire; Karin N Westlund Journal: Mol Pain Date: 2009-08-20 Impact factor: 3.395