title: Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin.
abstract: BACKGROUND
  Thymic stromal lymphopoietin (TSLP) is a cytokine with pleiotropic functions in the immune system. It has been associated with allergic reactions in the skin and lungs but also homeostatic tolerogenic responses in the thymus and gut.
  
  
  OBJECTIVE
  In human subjects TSLP is present in 2 isoforms, short and long. Here we wanted to investigate the differential expression of the TSLP isoforms and discern their biological implications under homeostatic or inflammatory conditions.
  
  
  METHODS
  We evaluated the expression of TSLPs in tissues from healthy subjects, patients with ulcerative colitis, patients with celiac disease, and patients with atopic dermatitis and on epithelial cells and keratinocytes under steady-state conditions or after stimulation. We then tested the immune activity of TSLP isoforms both in vitro and in vivo.
  
  
  RESULTS
  We showed that TSLP isoforms are responsible for 2 opposite immune functions. The short isoform is expressed under steady-state conditions and exerts anti-inflammatory activities by affecting the capacity of PBMCs and dendritic cells to produce inflammatory cytokines. Moreover, the short isoform TSLP ameliorates experimental colitis in mice and prevents endotoxin shock. The long isoform of TSLP is proinflammatory and is only expressed during inflammation. The isoforms are differentially regulated by pathogenic bacteria, such as Salmonella species and adhesive-invasive Escherichia coli.
  
  
  CONCLUSIONS
  We have solved the dilemma of TSLP being both homeostatic and inflammatory. The TSLP isoform ratio is altered during several inflammatory disorders, with strong implications in disease treatment and prevention. Indeed, targeting of the long isoform of TSLP at the C-terminal portion, which is common to both isoforms, might lead to unwanted side effects caused by neutralization of the homeostatic short isoform.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fornasa
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Katerina
authors.initials: K
authors.lastname: Tsilingiri
authors.affiliation: Unità Operativa Gastroenterologia ed Endoscopica, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico di Milano and Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.affiliation: Unità Operativa Gastroenterologia ed Endoscopica, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico di Milano and Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy.
authors.forename: Fiorenzo
authors.initials: F
authors.lastname: Botti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mapelli
authors.affiliation: Department of Dermatology, Medical Faculty, University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.affiliation: Department of Dermatology, Medical Faculty, University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kislat
authors.affiliation: Department of Dermatology, Medical Faculty, University of Dusseldorf, Düsseldorf, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.affiliation: First Department of Medicine, St Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Sabatino
authors.affiliation: Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Sonzogni
authors.affiliation: Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Viale
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Diaferia
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gori
authors.affiliation: Istituto di Chimica del Riconoscimento Molecolare, CNR, Milan, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penna
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy; Dipartimento di Scienze della Salute, San Paolo, Università degli Studi di Milano, Milan, Italy. Electronic address: maria.rescigno@ieo.eu.
authors.forename: Maria
authors.initials: M
authors.lastname: Rescigno
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007422:Intestines / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D012475:Salmonella / Q000276:immunology; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D012867:Skin / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D020033:Protein Isoforms; D000094632:Thymic Stromal Lymphopoietin
keywords: Thymic stromal lymphopoietin; anti-inflammatory drugs; atopic dermatitis; celiac disease; gut homeostasis; skin homeostasis; ulcerative colitis