Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis

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-α, and IL-1β). Site-directed mutagenesis revealed that Pin1-mediated transcriptional activation of COX-2 was coordinately regulated by NF-κB, CREB, and C/EBP. Gel shift, reporter gene, and Western blot analyses confirmed that NF-κB, 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-κB, CREB, and C/EBP, and suggest that Pin1 is a potential therapeutic target of RA.

PIN1 Inhibition Suppresses Osteoclast Differentiation and Inflammatory Responses

“…Up-regulation of PIN1 was also observed in radiation-exposed mouse skin tissues and JB6 Cl41 epidermal cells (Han et al 2011) and in chondrocytes, lymphocytes, and fibroblasts from RA lesions in mice with type II collagen-induced RA (Jeong HG et al 2009). Since PIN1 is up-regulated in periodontitis patients and nicotineand LPS-stimulated PDLCs, we evaluated PIN1 as a potential target for periodontitis.…”

“…Similarly, NF-κB activation in PIN1-overexpressing chondrocytes is associated with overproduction of proinflammatory mediators in RA progression (Jeong HG et al 2009). It was recently reported that Pin1 -/-mice exhibit a defect in bone morphogenetic protein signaling in osteoblasts but normal osteoclast function (Shen et al 2013).…”

“…In vivo inhibition of PIN1 by juglone reduced eosinophilic pulmonary inflammation in rat asthma (Esnault et al 2007), rat allergic lung fibrosis (Shen et al 2008), kidney fibrosis in rat ureteral occlusion (Reese et al 2010), and inflammation in mice with type II collagen-induced rheumatoid arthritis (RA; Jeong HG et al 2009). In vitro inhibition of PIN1 by juglone and PIN1 small-interfering RNA (siRNA) blocked ultraviolet A radiation-stimulated COX-2 expression and PGE 2 production in mouse epidermal cells (Quyen et al 2013) and decreased COX-2 expression in primary cultured chondrocytes from RA patients (Jeong HG et al 2009). However, PIN1 knockdown in endothelial cells increased COX-2 induction and PGE 2 production by LPS/interferon (Liu et al 2009).…”

The Peptidyl-prolyl Isomerase Pin1 Up-regulation and Proapoptotic Function in Dopaminergic Neurons

“…Esnault et al (59) showed that juglone prevented acute and chronic rejection of MHC mismatched, orthotopic rat lung transplants by reducing the expression of IFN-␥ and CXCL-10 mRNA stability, accumulation, and protein expression after cell activation. Another report showed that juglone at a dose of 5 mg/kg can attenuate rheumatoid arthritis development and COX-2 expression in human primary cultured RA chondrocytes and in type II collagen (CII)-treated DBA/1J mice (60). In our study we injected juglone (3 mg/kg) intraperitoneally to C57BL/6 mice, which attenuated MPTP-induced expression of Pin1 in nigrostriatal axis (Figs.…”

“…We employed a known inhibitor of Pin1, juglone, to determine the neuroprotective efficacy of the compound in an established MPTP model of PD. Juglone (5-hydroxy-1,4-napthalenedione (C 10 H 6 O 3 )), an aromatic organic napthoquinone naturally found in the leaves, roots, and bark of black walnut plants, has been widely used as a Pin1 inhibitor (59,60). Juglone irreversibly inactivates enzymatic activity of human Pin1 by modification of thiol groups of cysteine residues (61).…”