Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation

Thymic stromal lymphopoietin (TSLP) is a novel cytokine that was found to p romote the development of murine B cells in vitro. Here we describe the clo ning and characterization of the human homologue of murine TSLP. This prote in, which is expressed in a number of tissues including heart, liver and pr ostate, prevented apoptosis and stimulated growth of the human acute myeloi d leukemia (AML)-derived cell line MUTZ-3. Anti-Interleukin (IL)-7 receptor antibodies (Abs) neutralized this effect indicating that TSLP binds to at least part of the IL-7 receptor complex. TSLP induced phosphorylation of si gnal transducer and activator of transcription (STAT)-5. In contrast to IL- 7, TSLP-triggered STAT-5 phosphorylation was not preceded by activation of janus kinase (JAK) 3. These findings would be in accordance with the notion , raised previously for the mouse system, that TSLP leads to STAT-5 phospho rylation by activating other kinases than the JAKs. Some other signaling pa thways stimulated by many cytokines are not involved in TSLP activity; thus , TSLP did not stimulate activation of ERK1,2 and p70S6K. Furthermore, neut ralizing Abs raised against cytokines known to stimulate the growth of MUTZ -3 cells did not inhibit the proliferative effects of TSLP, suggesting that TSLP-induced growth was a direct effect. In summary, we describe the cloni ng of human TSLP and its proliferative effects on a myeloid cell line. TSLP -induced proliferation is preceded by phosphorylation of STAT-5, but not of JAK 3.