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Lacking the Nuclear Localization Signal as an Effective Gene Therapeutic Strategy in Collagen-Induced Arthritis1
* Department of Microbiology and Immunology,
Department of Biochemistry and Molecular Biology, and
Section of Rheumatology and Immunology, Department of Internal Medicine, National Cheng Kung University Medical College, Tainan, Taiwan
Prothymosin 
(ProT) is regulated by c-Myc, an oncoprotein overexpressed in synovium of rheumatoid arthritis, and is associated with cell proliferation. However, ProT also exerts immunomodulatory activities. The growth-promoting activity of ProT can be abolished by deleting its nuclear localization signal (NLS). In this study, we showed that AdProT
NLS, an adenoviral vector encoding ProT lacking the NLS, did not enhance the proliferation of synovial fibroblasts. AdProTNLS treatment abolished the up-regulation of the MIP-1 promoter activity induced by TNF- in synovial fibroblasts. AdProTNLS suppressed macrophage chemotaxis and reduced macrophage infiltration into the ankle joints in rats with collagen-induced arthritis (CIA). Neutralization test confirmed the involvement of MIP-1 in macrophage chemotaxis. Administration of AdProTNLS reduced the severity of CIA in the clinical, radiographic, and histological aspects. The levels of TNF- (mean ± SEM, 1261.9 ± 107.9 vs 2880.1 ± 561.4 pg/mg total protein; p < 0.05), IL-1
(56.8 ± 8.0 vs 109.2 ± 4.9 pg/mg total protein; p < 0.01), and MIP-1 (41.7 ± 3.6 vs 55.2 ± 1.1 pg/mg total protein; p < 0.05) in the ankle joints were lower in the AdProTNLS-treated rats with CIA than those in their control counterparts. In the AdProTNLS-treated ankle joints, matrix metalloproteinase-9 expression was decreased by 40% and infiltrating macrophages reduced by 50%. Our results demonstrate that intra-articular delivery of AdProTNLS significantly ameliorated the clinical course of CIA in rats. This study is the first to suggest that ProT lacking the NLS may have therapeutic potential for the management of rheumatoid arthritis.
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 NSC 92-2320-B-006-095, NSC 93-2320-B-006-080, and NSC 94-2311-B-006-006 (to C.-L.W.) from the National Science Council, Taiwan, and by the Foundation of Dr. Chen, Jieh-Chen Scholarship, Tainan, Taiwan.
2 Address correspondence and reprint requests to Dr. Chao-Liang Wu, Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, 1 Dashiue Road, Tainan 701, Taiwan; E-mail address: wumolbio{at}mail.ncku.edu.tw or Dr. Chrong-Reen Wang, Department of Internal Medicine, National Cheng Kung University Medical College, 1 Dashiue Road, Tainan 701, Taiwan; E-mail address: wangcr{at}mail.ncku.edu.tw
3 Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; MMP, matrix metalloproteinase; MOI, multiplicity of infection; NLS, nuclear localization signal; OA, osteoarthritis; ProT, prothymosin .
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