Abstract
Signaling through the interleukin 2 receptor (IL-2R) involves phosphorylation of several proteins including Jak3, STAT5, and, in preactivated cells, STAT3. In the present study, we examined the functional status of the IL-2R-associated Jak/STAT pathway in malignant T lymphocytes from advanced skin-based lymphomas: anaplastic large T-cell lymphoma (ALCL) and Sezary syndrome (SzS). Proliferation of three ALCL cell lines (PB-1, 2A, and 2B) was partially inhibited by rapamycin, a blocker of some of the signals mediated by IL-2R, but not by cyclosporin A, FK-506, and prednisone, which suppress signals mediated by the T-cell receptor. All the cell lines expressed on their surface the high-affinity IL-2R (α, γ, and γc chains). They showed basal, constitutive phosphorylation, and coassociation of Jak3, STAT5, and STAT3. Weak basal phosphorylation of IL-2R γc was also detected. In regard to SzS, peripheral blood mononuclear cells from 10 of 14 patients showed basal phosphorylation of Jak3, accompanied by phosphorylation of STAT5 in 9 patients, and STAT3 in 4 patients. However, in vitro overnight culture of SzS cells without exogenous cytokines resulted in markedly decreased Jak3 and STAT5 phosphorylation, which could be reversed by stimulation with IL-2. This indicates that the basal phosphorylation of Jak3 and STAT5 in freshly isolated SzS cells is induced rather than constitutive. The basal activation of the Jak/STAT pathway involved in IL-2R signal transduction in ALCL and SzS cells reported here suggests that this pathway may play a role in the pathogenesis of cutaneous T-cell lymphomas, although the mechanism (induced versus constitutive) may vary between different lymphoma types.
Original language | English |
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Pages (from-to) | 9148-9153 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 93 |
Issue number | 17 |
DOIs | |
State | Published - Aug 20 1996 |
Keywords
- Cell Membrane/metabolism
- Cyclosporine/pharmacology
- DNA-Binding Proteins/metabolism
- Humans
- Immunosuppressive Agents/pharmacology
- Janus Kinase 3
- Lymphocyte Activation
- Lymphoma, T-Cell, Cutaneous/etiology
- Milk Proteins
- Phosphorylation
- Polyenes/pharmacology
- Prednisone/pharmacology
- Protein Binding
- Protein-Tyrosine Kinases/metabolism
- Receptors, Interleukin-2/metabolism
- STAT3 Transcription Factor
- STAT5 Transcription Factor
- Sezary Syndrome/etiology
- Signal Transduction
- Sirolimus
- Tacrolimus/pharmacology
- Trans-Activators/metabolism
- Tumor Cells, Cultured/drug effects