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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901431v1 183/10/6689    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Jeong, H. G. Articles by Kang, K. W. PubMed PubMed Citation Articles by Jeong, H. G. Articles by Kang, K. W.

Novel Role of Pin1 Induction in Type II Collagen-Mediated Rheumatoid Arthritis¹

Hye Gwang Jeong,^2* Yuba Raj Pokharel,^2* Sung Chul Lim, Yong Pil Hwang,^* Eun Hee Han,^* Jung-Hoon Yoon, Sang-Gun Ahn, Kwang Yeol Lee,^¶ and Keon Wook Kang^3*

^*BK21 Project Team, College of Pharmacy, Chosun University, Gwangju and College of Pharmacy, Chungnam National University, Daejeonj, Department of Pathology, College of Medicine, Chosun University, Gwangju, South Korea; Department of Pathology, College of Dentistry, Chosun University, Gwangju; and ^¶College of Pharmacy, Chonnam University, Gwangju, South Korea

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

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from SRC/ERC program of Ministry of Science and Technology/KOSEF (Seoul National University, R11-2007-107-01002-0).

² H. G. J. and Y. R. P. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Keon Wook Kang, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea. E-mail address: kwkang{at}chosun.ac.kr

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; CII, type II collagen; COX-2, cyclooxygenase-2; CRE, cAMP response element; iNOS, inducible NO synthase; MSCV, murine stem cell virus; siRNA, small interfering RNA.