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The Effect of the JNK Inhibitor, JIP Peptide, on Human T Lymphocyte Proliferation and Cytokine Production¹

Michelle Melino^*,, Charles S. Hii^,, Shaun R. McColl^* and Antonio Ferrante^2,,

^* School of Molecular and Biomedical Sciences and School of Paediatrics and Reproductive Medicine, University of Adelaide, Adelaide, South Australia, and Department of Immunopathology, Children, Youth and Women’s Health Service, North Adelaide, South Australia, Australia

Although JNK is a potential target for treating chronic inflammatory diseases, its role in T lymphocyte function remains controversial. To overcome some of the previous limitations in addressing this issue we have used the recently described transactivator of transcription-JNK-interacting protein (TAT-JIP) peptide, a specific inhibitor that was derived from the minimal JNK-binding region of the scaffold protein, JNK-interacting protein 1 (JIP-1), coupled to the short cell-permeable HIV TAT sequence. Pretreatment of purified human T lymphocytes with the TAT-JIP peptide inhibited the phosphorylation of endogenous jun activated by PHA-PMA. This was associated with a corresponding inhibition of lymphoproliferation, and of IL-2, IFN-, lymphotoxin, and IL-10 cytokine production. Similar results were also found using mouse splenic T cells. Examination of the specificity of TAT-JIP revealed that although the peptide was more selective than the pharmacological inhibitor, SP600125, it also inhibited cyclin-dependent kinase 2, p70 ribosomal protein S6 kinase, and serum and glucocorticoid-regulated kinase activity. Nevertheless, these data demonstrate for the first time the ability of the TAT-JIP peptide to inhibit the JNK pathway and the phosphorylation of jun in intact cells, thereby preventing the activation of the transcription factor, AP-1, and the production of Th1 and Th2 cytokines. Thus JNK could potentially be a target for the development of drugs for the treatment of autoimmune inflammatory diseases.

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 the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Antonio Ferrante, Children, Youth and Women’s Health Service, 72 King William Road, North Adelaide, South Australia 5006, Australia. E-mail address: antonio.ferrante{at}adelaide.edu.au

³ Abbreviations used in this paper: MKK, MAPK kinase; TAT-JIP, transactivator of transcription-JNK-interacting protein; CK1, casein kinase 1; p70S6K, p70 ribosomal protein S6 kinase; Rsk1, ribosomal protein S6 kinase 1; SGK, serum and glucocorticoid-regulated kinase; DYRK, dual-specificity tyrosine-phosphorylated and regulated kinase; CDK2, cyclin dependent kinase 2.