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Klotho—a Common Link in Physiological and Rheumatoid Arthritis-Related Aging of Human CD4⁺ Lymphocytes¹

Jacek M. Witkowski^2,*, Monika Soroczyska-Cybula^*, Ewa Bryl^*, aneta Smoleska and Agnieszka Jówik^*

^* Department of Pathophysiology, Medical University of Gdask, Gdask, Poland; and Rheumatology Hospital, Sopot, Poland

Human CD4⁺ T lymphocytes undergo aging-related changes leading to decreased immunity to infections and neoplasms, and to increased frequency of autoimmune diseases including rheumatoid arthritis (RA). Certain changes, observed in the CD4⁺ cells of RA patients, resemble those observed during physiological aging, but occur at earlier age. Underlying cellular mechanism(s) of these similarities are so far largely unknown. Here we show that KLOTHO, a -glucuronidase gene whose activity changes are associated with aging phenotype, is down-regulated at the mRNA, protein, and enzymatic (-glucuronidase) activity levels both in the healthy elderly and especially in RA CD4⁺ lymphocytes. Although the exact role of Klotho activity for CD4⁺ cell function is unknown, we propose here that it might be involved in anti-inflammatory processes occurring in the young and healthy individuals, but reduced in both healthy elderly and RA patients. To support this hypothesis, we show here that the reduction of Klotho expression and activity in both elderly and patients’ lymphocytes occurs in concert with the down-regulation of T cell costimulatory molecule CD28, the latter known to be dependent on increased levels of TNF-. Thus, a common mechanism of KLOTHO down-regulation, but executed at various times in life, may underlie both physiological and disease-related T cell aging. Klotho activity might become a target of anti-RA drug development as well as a tool to help increase the immune system efficiency in the elderly.

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 a Polish State Committee for Scientific Research Grant P05B 039 22 (to J.M.W.).

² Address correspondence and reprint requests to Dr. Jacek M. Witkowski, Department of Pathophysiology, Medical University of Gdask, Debinki 7, 80-211 Gdansk, Poland. E-mail address: jawit{at}amg.gda.pl

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CQ, chloroquine; DAS, disease activity score; DSL, di-saccharolactone; KAAL, Klotho-associated -like sequence; MFI, mean fluorescence intensity.