Thymic Stromal Lymphopoietin: To Cut a Long Story Short

Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform. Thymic stromal lymphopoietin (TSLP) was identified more than 20 years ago as a secreted factor of a mouse thymic stromal cell line; later, a human orthologue was also identified. The signaling pathway triggered by TSLP has been extensively studied, and upregulation of the cytokine itself is linked to the pathogenesis of numerous Th2-related diseases, including atopic dermatitis, asthma, allergic responses, as well as certain types of cancers. On the other hand, TSLP mediates several immune homeostatic functions in both the gut and the thymus. Thus, a paradox occurs; why is TSLP homeostatic in certain tissues and a hallmark of exacerbated Th2 responses in the aforementioned pathologies? We and others have recently shown that in humans a novel isoform exists; this is a shorter isoform of TSLP whose expression is constitutive and controlled by a separate promoter. Short TSLP isoform mediates the homeostatic functions, whereas the long isoform is expressed at low/undetectable level at steady state and upregulated during inflammation in several tissues. Here we review the most recent data concerning the differential expression of the 2 isoforms and provide a potential explanation to the paradox. TSLP is regarded as a promising target for treatment of relevant pathologies, with a number of clinical trials already underway. It is important to design new strategies aimed at leaving intact the homeostatic effects of the short isoform while targeting the inflammatory effects of the long isoform. SummaryTSLP is a cytokine involved in a plethora of physiologic and pathologic immune functions, including tolerance and allergy. The existence of two isoforms of the protein whose expression is driven by independent promoters can explain these contrasting activities. TSLP is a cytokine involved in a plethora of physiologic and pathologic immune functions, including tolerance and allergy. The existence of two isoforms of the protein whose expression is driven by independent promoters can explain these contrasting activities. Cytokines (cyto, from Greek κύτταρο kyttaro “cell” + kines, from Greek κίνηση kinisi “movement”) are a broad category of small proteins whose release has an effect on the behavior of cells around them. They can act in an autocrine, paracrine, and/or endocrine fashion and are important in a number of biological processes including developmental processes during embryogenesis; however, they are particularly important in the regulation of immune responses. Cytokine types include chemokines, interferons (IFNs), lymphokines, interleukins (ILs), and tumor necrosis factors (TNFs). Because cytokines are important in intercellular and intracellular communications, they are produced by a broad range of cells such as fibroblasts, stromal, endothelial, or immune cells. They can be part of a physiological, homeostatic response or act as danger signals initiating inflammation in response to the detection of pathogens. Indeed, different isoforms of the same cytokine have been observed to mediate different effects according to the context, cellular source, and targets. These isoforms can be the result of alternative splicing, as is the case for IL15,1Onu A. Pohl T. Krause H. et al.Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms.J Immunol. 1997; 158: 255-262PubMed Google Scholar, 2Nishimura H. Yajima T. Naiki Y. et al.Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo.J Exp Med. 2000; 191: 157-170Crossref PubMed Scopus (132) Google Scholar or result from the expression of separate genes for each isoform, as is the case for the IFN, IL283Sheppard P. Kindsvogel W. Xu W. et al.IL-28, IL-29 and their class II cytokine receptor IL-28R.Nat Immunol. 2003; 4: 63-68Crossref PubMed Scopus (1309) Google Scholar and IL17.4Li H. Chen J. Huang A. et al.Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family.Proc Natl Acad Sci U S A. 2000; 97: 773-778Crossref PubMed Scopus (278) Google Scholar Here we will examine how thymic stromal lymphopoietin (TSLP) belongs to the category of cytokines with more than 1 isoform, and we will review recent data that shed light on a paradox: despite the necessity for TSLP in the homeostatic development of certain immune cell subsets, the same cytokine seems to exert potent proinflammatory actions, and its upregulation underlies numerous allergic reactions and allergy-related pathologies. TSLP is an IL7-like cytokine initially discovered in the culture supernatant of a mouse thymic stromal cell line and shown to act as a growth factor for T and B cells.5Friend S.L. Hosier S. Nelson A. et al.A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells.Exp Hematol. 1994; 22: 321-328PubMed Google Scholar The existence of a human orthologue with similar functions was shown some years later by Quentmeier et al,6Quentmeier H. Drexler H.G. Fleckenstein D. et al.Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.Leukemia. 2001; 15: 1286-1292Crossref PubMed Scopus (150) Google Scholar who observed constitutive TSLP expression in heart, lung, prostate, and testis human tissues. In the same study the authors cloned human TSLP and characterized the signaling pathway triggered by the TSLP–thymic stromal lymphopoietin protein receptor (TSLPR) interaction. In both human and mouse, the receptor for TSLP is a heterodimer composed of a chain specific for TSLP and the IL7R α-chain6Quentmeier H. Drexler H.G. Fleckenstein D. et al.Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.Leukemia. 2001; 15: 1286-1292Crossref PubMed Scopus (150) Google Scholar, 7Park L.S. Martin U. Garka K. et al.Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor.J Exp Med. 2000; 192: 659-670Crossref PubMed Scopus (326) Google Scholar, 8Pandey A. Ozaki K. Baumann H. et al.Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin.Nat Immunol. 2000; 1: 59-64Crossref PubMed Scopus (341) Google Scholar; however, in contrast to IL7, TSLP signaling results in JAK3-independent STAT5 phosphorylation.6Quentmeier H. Drexler H.G. Fleckenstein D. et al.Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.Leukemia. 2001; 15: 1286-1292Crossref PubMed Scopus (150) Google Scholar, 7Park L.S. Martin U. Garka K. et al.Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor.J Exp Med. 2000; 192: 659-670Crossref PubMed Scopus (326) Google Scholar Quentmeier et al observed that myeloid cells proliferate in response to human TSLP. These cell lines also upregulate granulocyte-macrophage colony-stimulating factor after conditioning; however, the authors demonstrate a direct effect of TSLP on the proliferation, independent from granulocyte-macrophage colony-stimulating factor and from the activity of mitogen-activated protein kinases (MAPKs).6Quentmeier H. Drexler H.G. Fleckenstein D. et al.Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation.Leukemia. 2001; 15: 1286-1292Crossref PubMed Scopus (150) Google Scholar TSLP also promotes the maturation of primary cells of myeloid origin, particularly CD11c+ dendritic cells (DCs), one of the subsets on expression of IL7R and is et thymic stromal lymphopoietin myeloid Immunol. 2001; PubMed Scopus Google Scholar, H. et cells dendritic cell allergic inflammation by Immunol. PubMed Scopus Google Scholar TSLP is expressed by cells and in the et thymic stromal lymphopoietin myeloid Immunol. 2001; PubMed Scopus Google Scholar and P. et thymic stromal lymphopoietin the and immune responses via and Th2 PubMed Scopus Google Scholar and seems to be involved in the regulation of inflammatory processes at the It is also produced by the cells of in the and dendritic cells to different types of T et dendritic cells to T cells in human PubMed Scopus Google Scholar, S. T. et stromal dendritic cells the of T cells in human Immunol. PubMed Scopus Google Scholar recent that other types of such as H. et cells dendritic cell allergic inflammation by Immunol. PubMed Scopus Google Scholar, Y. S. H. et thymic stromal lymphopoietin by human J. PubMed Scopus Google Scholar Thymic stromal lymphopoietin and Immunol. PubMed Scopus Google Scholar et al.A for the of T 2 Immunol. PubMed Scopus Google Scholar and Y. et stromal lymphopoietin is produced by dendritic Immunol. PubMed Scopus Google Scholar In can be of TSLP certain on in vitro of by and a upregulation of TSLP mRNA expression in a In with a for responses, TSLP by both and dendritic cells in the Y. et stromal lymphopoietin is produced by dendritic Immunol. PubMed Scopus Google Scholar more recent TSLP by human after with on The authors that is for TSLP and that this of both factor B and the et by dendritic cells is by and of the Immunol. 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