Abstract
Progranulin (PGRN) is a recently identified adipokine that is supposed to have anti-inflammatory actions. The proinflammatory cytokine interleukin-1β (IL1β) stimulates several mediators of cartilage degradation. Toll like receptor-4 (TLR4) can bind to various damage-associated molecular patterns, leading to inflammatory condition. So far, no data exist of PGRN effects in inflammatory conditions induced by IL1β or lipopolysaccharide (LPS). Here, we investigated the anti-inflammatory potential of PGRN in IL1β- or LPS-induced inflammatory responses of chondrocytes. Human osteoarthritic chondrocytes and ATDC-5 cells were treated with PGRN in presence or not of IL1β or LPS. First, we showed that recombinant PGRN had no effects on cell viability. We present evidence that PGRN expression was increased during the differentiation of ATDC-5 cell line. Moreover, PGRN mRNA and protein expression is increased in cartilage, synovial and infrapatellar fat pad tissue samples from OA patients. PGRN mRNA levels are upregulated under TNFα and IL1β stimulation. Our data showed that PGRN is able to significantly counteract the IL1β-induced expression of NOS2, COX2, MMP13 and VCAM-1. LPS-induced expression of NOS2 is also decreased by PGRN. These effects are mediated, at least in part, through TNFR1. Taken together, our results suggest that PGRN has a clear anti-inflammatory function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cartilage, Articular / metabolism
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Cell Differentiation / drug effects
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Cell Line
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Cell Survival / drug effects
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Chondrocytes / cytology
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Chondrocytes / metabolism
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Cyclooxygenase 2 / metabolism
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Down-Regulation / drug effects
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Intercellular Signaling Peptides and Proteins / pharmacology*
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Interleukin-1beta / pharmacology*
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Lipopolysaccharides / toxicity
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Matrix Metalloproteinase 13 / metabolism
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Mice
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Osteoarthritis / metabolism
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Osteoarthritis / pathology
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Progranulins
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Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism*
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / pharmacology
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Synovial Membrane / metabolism
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Toll-Like Receptor 4 / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Up-Regulation / drug effects
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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GRN protein, human
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Intercellular Signaling Peptides and Proteins
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Interleukin-1beta
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Lipopolysaccharides
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Progranulins
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Proteins
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Cyclooxygenase 2
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Matrix Metalloproteinase 13