Disease relevance of TSLP

• TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis [1].
• TSLP and TARC/CCL17 expression correlated with airway obstruction [2].
• Thymic stromal lymphopoietin (TSLP) transgenic mice develop mixed cryoglobulinemia and a membranoproliferative glomerulonephritis (MPGN) [3].
• The direct link between TSLP expression with the pathogenesis of atopic dermatitis and asthma in vivo was demonstrated [4].

High impact information on TSLP

• Thymic stromal lymphopoietin conditions dendritic cells to support homeostatic proliferation of central memory T cells [5].
• Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells [6].
• Only dendritic cells (DCs) activated by thymic stromal lymphopoietin (TSLP) can induce a robust expansion of CRTH2+CD4+ TH2 memory cells, while maintaining their central memory phenotype and TH2 commitments [6].
• We show here that TSLP expression was increased in the lungs of mice with antigen-induced asthma, whereas TSLP receptor-deficient mice had considerably attenuated disease [7].
• These results, together with findings of TSLP expression in epithelial cells of mucosal lymphoid tissues and thymus, indicate that TSLP is involved in DC-mediated CD4(+) T cell homeostasis [8].

Biological context of TSLP

• TSLP expression was associated with Langerhans cell migration and activation in situ [1].
• Thymic stromal lymphopoietin (TSLP) is a newly identified cytokine that uniquely promotes B lymphopoiesis to the B220+/IgM+ immature B cell stage [9].
• Cells transfected with both receptor subunits proliferated in response to purified, recombinant human TSLP, with induced phosphorylation of Stat3 and Stat5 [10].
• Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction [9].
• Human thymic stromal lymphopoietin (TSLP) is a novel epithelial cell-derived cytokine, which induces dendritic cell (DC)-mediated CD4+ T cell responses with a proallergic phenotype [11].

Anatomical context of TSLP

• Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP [1].
• These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation [1].
• Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells [2].
• Epithelial cells, endothelial cells, neutrophils, macrophages, and mast cells were significant sources of TSLP and chemokines [2].
• Thymic stromal lymphopoietin (TSLP) is a cytokine that facilitates B lymphocyte differentiation and costimulates T cells [12].

Associations of TSLP with chemical compounds

• In addition, TSLP shares many biological properties with the related cytokine IL-7 [9].
• The combination of TNF-alpha and IL-4 produced detectable levels of TSLP protein (40 +/- 13 pg/ml) [13].

Physical interactions of TSLP

• Human TSLP is proposed to signal through a heterodimeric receptor complex that consists of a new member of the hemopoietin family termed human TSLP receptor and the IL-7R alpha-chain [10].

Enzymatic interactions of TSLP

• Because Stat5 phosphorylation following cytokine stimulation is generally mediated by Jaks, the lack of Jak activation after TSLP treatment suggested the possibility that tyrosine-phosphorylated Stat5 may be nonfunctional [9].

Regulatory relationships of TSLP

• IL-7R alpha-expressing but not parental 32D cells proliferate in the presence of exogenous TSLP [14].
• Human TSLP promotes CD40 ligand-induced IL-12 production by myeloid dendritic cells but maintains their Th2 priming potential [15].
• TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand [16].

Other interactions of TSLP

• Moreover, TSLP-mediated signaling is inhibited by suppressor of cytokine signaling (SOCS)-1 and a kinase-deficient version of Tec but not by kinase-deficient forms of Jak1 and Jak2 [9].
• Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells [11].
• Here, we show that TSLP-activated CD11c+ DCs potently activate and expand naive CD8+ T cells, and induce their differentiation into interleukin (IL)-5 and IL-13-producing effectors exhibiting poor cytolytic activity [11].
• Epithelial human TSLP activates DC, which allow them to prime naive T cells for the production of pro-inflammatory cytokines, while down-regulating IFN-gamma and IL-10 [17].
• Gene expression profiles screened a variety of molecules that are triggered by TSLP with or without CD40 ligation [18].

Analytical, diagnostic and therapeutic context of TSLP

• These transgenic mice demonstrate that TSLP can initiate a cascade of allergic inflammation in the skin and provide a valuable animal model for future study of this common disease [19].
• Expression of chemokines at protein levels and enzymatic activity of indoleamine 2,3-dioxygenase was further confirmed to increase in the presence of TSLP using ELISA and HPLC, respectively [18].
• Immunohistochemistry studies reveal that CD25(+)CTLA4(+) (cytotoxic T-lymphocyte-associated protein 4) regulatory T cells associate in the thymic medulla with activated or mature dendritic cells and TSLP-expressing Hassall's corpuscles [20].

References