The effect of the JNK inhibitor, JIP peptide, on human T lymphocyte proliferation and cytokine production.
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-gamma, 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.
Melino
Michelle
M
School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
Hii
Charles S
CS
McColl
Shaun R
SR
Ferrante
Antonio
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C520352:JNK-interacting protein 1 (153-163); D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; C470431:tat peptide (1-72), Human immunodeficiency virus 1; D048670:MAP Kinase Kinase 4