Abstract
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation in joints and subsequent destruction of cartilage and bone. Inflammatory mediators such as PGs and proinflammatory cytokines contribute to RA progress. Pin1, a peptidyl prolyl isomerase, plays important pathophysiological roles in several diseases, including cancer and neurodegeneration. We found that both Pin1 and cyclooxygenase-2 (COX-2) were highly expressed in ankle tissues of type II collagen-induced RA mice. HTB-94 cells overexpressing Pin1 and primary cultured human chondrocytes showed increased basal expression of proinflammatory proteins (COX-2, inducible NO synthase, TNF-alpha, and IL-1beta). Site-directed mutagenesis revealed that Pin1-mediated transcriptional activation of COX-2 was coordinately regulated by NF-kappaB, CREB, and C/EBP. Gel shift, reporter gene, and Western blot analyses confirmed that NF-kappaB, CREB, and C/EBP were consistently activated in chondrocytes overexpressing Pin1. Treatment of RA mice with juglone, a chemical inhibitor of Pin1, significantly reduced RA progress and COX-2 expression in the ankle tissues. Moreover, juglone dose dependently decreased the basal COX-2 expression in primary cultured chondrocytes from RA patients. These results demonstrate that Pin1 induction during RA progress stimulates proinflammatory protein expression by activating NF-kappaB, CREB, and C/EBP, and suggest that Pin1 is a potential therapeutic target of RA.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ankle Joint / drug effects
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Ankle Joint / immunology
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Ankle Joint / pathology
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Arthritis, Rheumatoid / drug therapy
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Arthritis, Rheumatoid / immunology*
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Cell Line
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Cells, Cultured
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Chondrocytes / drug effects
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Chondrocytes / immunology*
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Chondrocytes / metabolism
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Collagen Type II / pharmacology
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Cyclic AMP Response Element-Binding Protein / immunology
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclooxygenase 2 / drug effects
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Cyclooxygenase 2 / immunology
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Cyclooxygenase 2 / metabolism
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Genes, Reporter / genetics
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Genes, Reporter / immunology
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Humans
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Mice
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NF-kappa B / immunology
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NF-kappa B / metabolism
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NIMA-Interacting Peptidylprolyl Isomerase
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Naphthoquinones / administration & dosage
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Naphthoquinones / therapeutic use*
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Nitric Oxide Synthase Type II / immunology
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Nitric Oxide Synthase Type II / metabolism
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Peptidylprolyl Isomerase / antagonists & inhibitors
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Peptidylprolyl Isomerase / immunology*
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Peptidylprolyl Isomerase / metabolism
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Steroid Isomerases / immunology
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Steroid Isomerases / metabolism
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Transfection
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Collagen Type II
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Cyclic AMP Response Element-Binding Protein
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Interleukin-1beta
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NF-kappa B
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NIMA-Interacting Peptidylprolyl Isomerase
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Naphthoquinones
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Tumor Necrosis Factor-alpha
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NOS2 protein, human
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Nitric Oxide Synthase Type II
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Ptgs2 protein, mouse
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Cyclooxygenase 2
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PTGS2 protein, human
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PIN1 protein, human
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Peptidylprolyl Isomerase
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Pin1 protein, mouse
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Steroid Isomerases
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juglone