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.

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Thrombopoietin is the primary regulator of platelet production. We exploited two naturally occurring miniproteins of the inhibitor cystine knot family as stable and rigid scaffolds for the incorporation of peptide sequences that have been shown to act as high‐affinity thrombopoietin antagonists. Several miniproteins that antagonistically block thrombopoietin‐mediated receptor activation were identified using a microscale reporter assay. Covalent miniprotein dimerization yielded potent bivalent c‐Mpl receptor agonists with EC50 values in the low nanomolar or picomolar range. One selected miniprotein‐derived thrombopoietin agonist was almost as active as natural thrombopoietin with regard to stimulation of megakaryocyte colony formation from human bone marrow mononuclear cells, and elicited doubling of platelet counts in mice. Our data suggest that dimeric cystine knot miniproteins have considerable potential for the future development of small and stable receptor agonists. This approach may provide a promising strategy for pharmaceutical interference with other receptors activated by ligand‐induced dimerization.

SUMMARYInterleukin-13 (IL-13) is critical for the development of allergic asthma and is involved in the activation of eosinophils within the airways. IL-13 exerts its activity on target cells via the dimeric IL-13 receptor (IL-13R), which comprises the IL-13 receptor a1-chain (IL-13Ra1) as a specific component. The aim of this study was to investigate the expression of the IL-13Ra1-chain on primary human eosinophilic granulocytes. Furthermore, it addresses the regulatory influence of cytokines on the level of surface abundance of this receptor subunit. Expression of IL-13-and IL-4-receptor subunits in purified primary human eosinophils was monitored at the messenger RNA level by reverse transcription polymerase chain reaction and at the protein level by flow cytometry. For the analysis of IL-13Ra1 surface expression, a new monoclonal antibody, which was generated using genetic immunization, was employed. Different cytokines with established activity on eosinophils were studied with regard to their influence on IL-13Ra1 in vitro by flow cytometry. Whereas IL-13 and IL-4 had inhibitory effects on IL-13Ra1 expression on eosinophils, interferon-c, tumour necrosis factor-a, and, to the largest extent, transforming growth factor-b, enhanced the expression of this receptor subunit. A positive regulatory response evoked by transforming growth factor-b and interferon-c does not prevent inhibitory effects caused by IL-13. These findings suggest a regulatory cytokine network influencing the reactivity of eosinophils to IL-13.

Our findings indicate a function of IL-13 as a mediator in fibrotic processes leading to loss of functional airway tissue in asthma. They also highlight the therapeutic potential of specifically targeting the interaction between IL-13 and its receptor.