Thymic stromal lymphopoietin

Thymic stromal lymphopoietin (TSLP) is a protein belonging to the cytokine family. It is known to play an important role in the maturation of T cell populations through activation of antigen presenting cells.

TSLP
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4NN5, 4NN6, 4NN7
Identifiers
Aliases	TSLP, thymic stromal lymphopoietin
External IDs	OMIM: 607003 MGI: 1855696 HomoloGene: 81957 GeneCards: TSLP
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q22.1 Start 111,070,062 bp[1] End 111,078,026 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18 B1|18 18.12 cM Start 32,815,383 bp[2] End 32,819,797 bp[2]
Gene ontology Molecular function • cytokine activity • interleukin-7 receptor binding Cellular component • extracellular • extracellular region Biological process • regulation of receptor activity • interleukin-7-mediated signaling pathway • positive regulation of cytokine-mediated signaling pathway • positive regulation of cell proliferation • positive regulation of chemokine production • positive regulation of interleukin-10 production • positive regulation of interleukin-13 production • positive regulation of interleukin-5 production • positive regulation of interleukin-6 production • positive regulation of mast cell activation • positive regulation of tyrosine phosphorylation of STAT protein • negative regulation of apoptotic process • positive regulation of inflammatory response • defense response to Gram-negative bacterium • defense response to fungus • antimicrobial humoral immune response mediated by antimicrobial peptide • positive regulation of chemokine (C-C motif) ligand 1 production • positive regulation of granulocyte colony-stimulating factor production • positive regulation of STAT cascade • positive regulation of interleukin-5 secretion Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	85480	53603
Ensembl	ENSG00000145777	ENSMUSG00000024379
UniProt	Q969D9	Q9JIE6
RefSeq (mRNA)	NM_033035 NM_138551	NM_021367
RefSeq (protein)	NP_149024 NP_612561	NP_067342
Location (UCSC)	Chr 5: 111.07 – 111.08 Mb	Chr 18: 32.82 – 32.82 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

TSLP is produced mainly by non-hematopoietic cells such as fibroblasts, epithelial cells and different types of stromal or stromal-like cells. These cells are located in regions where TSLP activity is required.

Gene ontology

TSLP production has been observed in various species, including humans and mice. In humans TSLP is encoded by the TSLP gene.[5][6] Alternative splicing of this gene results in two transcript variants.[6]

Function

It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes and enhances the maturation of myeloid (CD11c+) dendritic cells.[7] TSLP has also been shown to activate the maturation of a specific subset of dendritic cells located within the epidermis, called Langerhans cells.[8] Within the thymus TSLP activation of both myeloid and plasmacytoid (CD123+) dendritic cells results in the production of regulatory T cells.[9][10]

Signaling

TSLP signals through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor CRLF2 and the IL-7R alpha chain. After binding STAT5 phosphorylation is induced resulting in the expression of upstream transcription factors.[11]

Disease

TSLP expression is linked to many disease states including asthma,[12] inflammatory arthritis,[13] atopic dermatitis,[8] eczema, eosinophilic esophagitis and other allergic states.[14][15] The factors inducing the activation of TSLP release are not clearly defined.

Asthma

Expression of TSLP is enhanced under asthma-like conditions (aka Airway HyperResponsiveness or AHR model in the mouse), conditioning APCs in order to orient the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway). The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways .

Inflammatory arthritis

Atopic dermatitis

TSLP-activated Langerhans cells of the epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis.[8] It is thought that understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema.[16]

References

1. GRCh38: Ensembl release 89: ENSG00000145777 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024379 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD (Aug 2001). "Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation". Leukemia. 15 (8): 1286–92. doi:10.1038/sj.leu.2402175. PMID 11480573.
6. "Entrez Gene: TSLP thymic stromal lymphopoietin".
7. Reche PA, Soumelis V, Gorman DM, et al. (July 2001). "Human thymic stromal lymphopoietin preferentially stimulates myeloid cells". J. Immunol. 167 (1): 336–43. doi:10.4049/jimmunol.167.1.336. PMID 11418668.
8. Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N (April 2007). "Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells". J. Allergy Clin. Immunol. 119 (4): 982–90. doi:10.1016/j.jaci.2007.01.003. PMID 17320941.
9. Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ (August 2005). "Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus". Nature. 436 (7054): 1181–5. doi:10.1038/nature03886. PMID 16121185.
10. Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, Arima K, Wang YH, Voo KS, Cao W, Liu YJ (March 2010). "Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus". J. Immunol. 184 (6): 2999–3007. doi:10.4049/jimmunol.0804106. PMC 3325785. PMID 20173030.
11. Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF (December 1999). "Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction". J. Immunol. 163 (11): 5971–7. PMID 10570284.
12. Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C (June 2005). "Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity". J. Immunol. 174 (12): 8183–90. doi:10.4049/jimmunol.174.12.8183. PMID 15944327.
13. Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, Suenaga F, Ohnuma Y, Ohba T, Katoh R, Sugiyama H, Hamada Y, Ogawa H, Okumura K, Nakao A (May 2007). "A possible role for TSLP in inflammatory arthritis". Biochem. Biophys. Res. Commun. 357 (1): 99–104. doi:10.1016/j.bbrc.2007.03.081. PMID 17416344.
14. Soumelis V, Liu YJ (February 2004). "Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation". Springer Semin. Immunopathol. 25 (3–4): 325–33. doi:10.1007/s00281-003-0152-0. PMID 14999427.
15. Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, Gilliet M, Ho S, Antonenko S, Lauerma A, Smith K, Gorman D, Zurawski S, Abrams J, Menon S, McClanahan T, de Waal-Malefyt Rd R, Bazan F, Kastelein RA, Liu YJ (July 2002). "Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP" (PDF). Nat. Immunol. 3 (7): 673–80. doi:10.1038/ni805. PMID 12055625.
16. Demehri S, Morimoto M, Holtzman MJ, Kopan R (May 2009). "Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma". PLoS Biol. 7 (5): e1000067. doi:10.1371/journal.pbio.1000067. PMC 2700555. PMID 19557146. Lay summary – BBC News.

Further reading

• Ziegler SF, Liu YJ (2006). "Thymic stromal lymphopoietin in normal and pathogenic T cell development and function". Nat. Immunol. 7 (7): 709–14. doi:10.1038/ni1360. PMID 16785889.
• Liu YJ (2007). "Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation". J. Allergy Clin. Immunol. 120 (2): 238–44, quiz 245–6. doi:10.1016/j.jaci.2007.06.004. PMID 17666213.
• Gilliet M, Soumelis V, Watanabe N, et al. (2003). "Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells". J. Exp. Med. 197 (8): 1059–63. doi:10.1084/jem.20030240. PMC 2193883. PMID 12707303.
• Watanabe N, Hanabuchi S, Marloie-Provost MA, et al. (2005). "Human TSLP promotes CD40 ligand-induced IL-12 production by myeloid dendritic cells but maintains their Th2 priming potential". Blood. 105 (12): 4749–51. doi:10.1182/blood-2004-09-3622. PMID 15741223.
• Lee HC, Ziegler SF (2007). "Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFkappaB". Proc. Natl. Acad. Sci. U.S.A. 104 (3): 914–9. doi:10.1073/pnas.0607305104. PMC 1783414. PMID 17213320.
• Zhang K, Shan L, Rahman MS, et al. (2007). "Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease". Am. J. Physiol. Lung Cell Mol. Physiol. 293 (2): L375–82. doi:10.1152/ajplung.00045.2007. PMID 17513456.
• Rochman I, Watanabe N, Arima K, et al. (2007). "Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells". J. Immunol. 178 (11): 6720–4. doi:10.4049/jimmunol.178.11.6720. PMID 17513717.
• Wang YH, Angkasekwinai P, Lu N, et al. (2007). "IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells". J. Exp. Med. 204 (8): 1837–47. doi:10.1084/jem.20070406. PMC 2118667. PMID 17635955.

External links

• Overview of all the structural information available in the PDB for UniProt: Q969D9 (Thymic stromal lymphopoietin) at the PDBe-KB.