Signal transduction by the atopy-associated human thymic stromal lymphopoietin (TSLP) receptor depends on Janus kinase function.
Thymic stromal lymphopoietin (TSLP) is an interleukin-(IL)-7-like cytokine with emerging pathological importance for the development of atopic diseases such as allergic asthma bronchiale. The TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor, shares the IL-7R alpha-subunit with the IL-7 receptor system. The specific TSLPR alpha-chain shows similarities with the gammac receptor chain, but has some unusual features within the receptor family in both its ligand-binding and cytoplasmic domain. The murine TSLPR signals via the signal transducers and activators of transcription STAT5 and STAT3, but is unique among cytokine receptors in that it activates STATs without the involvement of Janus (JAK) tyrosine kinases, but instead utilizes the Src type kinase Tec. Here, we show by Western blotting and reporter gene experiments in combination with the application of a specific JAK inhibitor that the human TSLP receptor, in contrast, requires the function of JAK1 and JAK2 for STAT activation. Moreover, we demonstrate that the human TSLPR mediates gene regulation not only through STAT5 and STAT3 but has also the potential to mediate transcription via STAT1. Our work should help to understand more thoroughly how TSLP triggers inflammatory responses in the course of atopic diseases.
Wohlmann
Andreas
A
Institute of Biochemistry II, University of Jena Medical School, Nonnenplan 2, D-07743 Jena, Germany.
Sebastian
Katrin
K
Institute of Biochemistry II, University of Jena Medical School, Nonnenplan 2, D-07743 Jena, Germany.
Borowski
Andreas
A
Institute of Biochemistry II, University of Jena Medical School, Nonnenplan 2, D-07743 Jena, Germany.
Krause
Sebastian
S
Institute of Biochemistry II, University of Jena Medical School, Nonnenplan 2, D-07743 Jena, Germany.
Friedrich
Karlheinz
K
Institute of Biochemistry II, University of Jena Medical School, Nonnenplan 2, D-07743 Jena, Germany.
D000818:Animals; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
C498762:CRLF2 protein, human; D047428:Protein Kinase Inhibitors; D018121:Receptors, Cytokine; D050791:STAT Transcription Factors; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2