title: TSLP production by dendritic cells is modulated by IL-1β and components of the endoplasmic reticulum stress response.
abstract: Thymic stromal lymphopoietin (TSLP) produced by epithelial cells acts on dendritic cells (DCs) to drive differentiation of TH 2-cells, and is therefore important in allergic disease pathogenesis. However, DCs themselves make significant amounts of TSLP in response to microbial products, but little is known about the key downstream signals that induce and modulate this TSLP secretion from human DCs. We show that human monocyte derived DC (mDC) secretion of TSLP in response to Candida albicans and β-glucans requires dectin-1, Syk, NF-κB, and p38 MAPK signaling. In addition, TSLP production by mDCs is greatly enhanced by IL-1β, but not TNF-α, in contrast to epithelial cells. Furthermore, TSLP secretion is significantly increased by signals emanating from the endoplasmic reticulum (ER) stress response, specifically the unfolded protein response sensors, inositol-requiring transmembrane kinase/endonuclease 1 and protein kinase R-like ER kinase, which are activated by dectin-1 stimulation. Thus, TSLP production by mDCs requires the integration of signals from dectin-1, the IL-1 receptor, and ER stress signaling pathways. Autocrine TSLP production is likely to play a role in mDC-controlled immune responses at sites removed from epithelial cell production of the cytokine, such as lymphoid tissue.
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Elder
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Webster
authors.affiliation: Department of Surgery, Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Williams
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK.
authors.forename: J S Hill
authors.initials: JS
authors.lastname: Gaston
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK.
authors.forename: Jane C
authors.initials: JC
authors.lastname: Goodall
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D002176:Candida albicans / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology*; D059865:Endoplasmic Reticulum Stress; D005936:Glucans / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D020239:Receptor Cross-Talk; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D051742:Transcription Factor CHOP / Q000235:genetics; D056811:Unfolded Protein Response; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000946:Antigens, Fungal; D016207:Cytokines; D005936:Glucans; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; D000094632:Thymic Stromal Lymphopoietin; C497250:Ddit3 protein, mouse; C033671:epiglucan
keywords: Dectin-1; ER stress; IL-1β; TSLP