Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation.
Thymic stromal lymphopoietin (TSLP) is highly expressed by bronchial epithelial cells and skin keratinocytes in allergic diseases. TSLP acts as a master switch for allergic inflammation through the activation of dendritic cells and mast cells for initiating inflammatory type 2 T-helper lymphocyte responses. To elucidate the immunological cascades of epithelium/keratinocyte-eosinophil-mediated allergic inflammation, we examined the modulating effects of TSLP on human eosinophils. Expression of TSLP receptor complex was detected by RT-PCR, flow cytometry, and Western blot. Adhesion molecules, cytokine, and chemokines were quantitated by flow cytometry or ELISA. Intracellular signal transduction molecules were measured by Western blot and flow cytometry. We observed that human eosinophils constitutively expressed functional heterodimeric TSLP receptor complex comprising TSLP-binding chain TSLPR and IL-7Ralpha chain. TSLP could significantly delay eosinophil apoptosis, up-regulate cell surface expression of adhesion molecule CD18 and intercellular adhesion molecule-1, but down-regulate L-selectin, enhance eosinophil adhesion onto fibronectin, and induce the release of inflammatory cytokine IL-6 and chemokines CXCL8, CXCL1, and CCL2 (all P < 0.05). All these effects were concentration dependent and TSLP specific. TSLP regulated the above effects through the activation of extracellular signal-regulated protein kinase, p38 mitogen-activated protein kinase, and NF-kappaB signaling pathway, but not signal transducer and activator of transcription 5 and 3, which were usually activated in other effector cells upon TSLP stimulation. Collectively, the above findings elucidate the proallergic mechanisms of TSLP via the activation of distinct intracellular signaling pathways in eosinophils.
Department of Chemical Pathology, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
Chun K
CK
Wong
Shuiqing
S
Hu
Phyllis F Y
PF
Cheung
Christopher W K
CW
Lam
D017209:Apoptosis; D001249:Asthma / Q000276:immunology*; D015153:Blotting, Western; D002448:Cell Adhesion; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000166:cytology* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000094632:Thymic Stromal Lymphopoietin
C498762:CRLF2 protein, human; D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D020928:Mitogen-Activated Protein Kinases; D000094632:Thymic Stromal Lymphopoietin