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TSLP (Thymic Stromal Lymphopoietin) è una citochina prodotta da cellule epiteliali timiche presenti nei corpuscoli di Hassal.




'''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 cell|antigen presenting cells]].

TSLP is produced mainly by non-[[Haematopoiesis|hematopoietic]] cells such as [[fibroblasts]], [[epithelium|epithelial cells]] and different types of [[stromal cell|stromal]] or stromal-like cells.{{Citation needed|date=September 2008}} 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]].<ref name="pmid11480573">{{cite journal | author = Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD | title = Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation | journal = Leukemia | volume = 15 | issue = 8 | pages = 1286–92 | year = 2001 | month = Aug | pmid = 11480573 | pmc = | doi = 10.1038/sj.leu.2402175}}</ref><ref name="entrez"/> [[Alternative splicing]] of this gene results in two transcript variants.<ref name="entrez">{{cite web | title = Entrez Gene: TSLP thymic stromal lymphopoietin| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=85480| accessdate = }}</ref>

== Function ==

It mainly impacts myeloid cells and induces the release of [[T cell]]-attracting chemokines from [[monocyte]]s {{Citation needed|date=January 2011}} and enhances the maturation of [[myeloid dendritic cells|myeloid]] (CD11c+) dendritic cells.<ref>{{cite journal |author=Reche PA, Soumelis V, Gorman DM, ''et al.'' |title=Human thymic stromal lymphopoietin preferentially stimulates myeloid cells |journal=J. Immunol. |volume=167 |issue=1 |pages=336–43 |year=2001 |month=July |pmid=11418668 |doi= |url=}}</ref> TSLP has also been shown to activate maturation of specific subset of dendritic cells located within the [[epidermis (skin)|epidermis]], [[Langerhans cell]].<ref name="pmid17320941">{{cite journal | author = Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N | title = Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells | journal = J. Allergy Clin. Immunol. | volume = 119 | issue = 4 | pages = 982–90 | year = 2007 | month = April | pmid = 17320941 | doi = 10.1016/j.jaci.2007.01.003 | url = | issn = }}</ref> Within the [[thymus]] TSLP activation of both myeloid and [[plasmacytoid dendritic cells|plasmacytoid]] (CD123+) dendritic cells results in the production of [[regulatory T cell]]s.<ref name="pmid16121185">{{cite journal | author = Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ | title = Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus | journal = Nature | volume = 436 | issue = 7054 | pages = 1181–5 | year = 2005 | month = August | pmid = 16121185 | doi = 10.1038/nature03886 | url = | issn = }}</ref><ref name="pmid20173030">{{cite journal | author = Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, Arima K, Wang YH, Voo KS, Cao W, Liu YJ | title = Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus | journal = J. Immunol. | volume = 184 | issue = 6 | pages = 2999–3007 | year = 2010 | month = March | pmid = 20173030 | doi = 10.4049/jimmunol.0804106 | url = | issn = | pmc=3325785}}</ref>

=== Signalling ===

TSLP signals through a heterodimeric receptor complex composed of the thymic stromal lymphopoietin receptor and the [[Interleukin-7 receptor-α|IL-7R alpha]] chain. After binding [[STAT5]] phosphorylation is induced resulting in the expression of downstream [[transcription factors]].<ref name="pmid10570284">{{cite journal | author = Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF | title = Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction | journal = J. Immunol. | volume = 163 | issue = 11 | pages = 5971–7 | year = 1999 | month = December | pmid = 10570284 | doi = | url = | issn = }}</ref>

== Disease ==

TSLP expression is linked to many disease states including asthma,<ref name="pmid15944327">{{cite journal | author = Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C | title = Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity | journal = J. Immunol. | volume = 174 | issue = 12 | pages = 8183–90 | year = 2005 | month = June | pmid = 15944327 | doi = | url = | issn = }}</ref> inflammatory arthritis,<ref name="pmid17416344">{{cite journal | author = 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 | title = A possible role for TSLP in inflammatory arthritis | journal = Biochem. Biophys. Res. Commun. | volume = 357 | issue = 1 | pages = 99–104 | year = 2007 | month = May | pmid = 17416344 | doi = 10.1016/j.bbrc.2007.03.081 | url = | issn = }}</ref> atopic dermatitis,<ref name="pmid17320941"/> and eczema and other allergic states.<ref name="pmid14999427">{{cite journal | author = Soumelis V, Liu YJ | title = Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation | journal = Springer Semin. Immunopathol. | volume = 25 | issue = 3-4 | pages = 325–33 | year = 2004 | month = February | pmid = 14999427 | doi = 10.1007/s00281-003-0152-0 | url = | issn = }}</ref><ref name="pmid12055625">{{cite journal | author = 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 | title = Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP | journal = Nat. Immunol. | volume = 3 | issue = 7 | pages = 673–80 | year = 2002 | month = July | pmid = 12055625 | doi = 10.1038/ni805 | url = | issn = }}</ref> The factors inducing the activation of TSLP release are not clearly defined.

=== Asthma ===
Expression of TSLP is enhanced under [[asthma]]-like conditions (aka [[bronchial hyperresponsiveness|Airway HyperResponsiveness]] or AHR model in the mouse), conditioning [[antigen-presenting cells|APCs]] in order to orientate the differentiation of T cells coming into the lungs towards a [[T helper cell|TH2]] profile (T helper 2 pathway).{{Citation needed|date=September 2008}} The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways {{Citation needed|date=January 2011}}.

=== Inflammatory arthritis ===
=== Atopic Dermatitis ===

TSLP-activated Langerhan cells of the [[epidermis (skin)|epidermis]] induce the production of [[pro-inflammatory cytokine]]s like [[TNF-alpha]] by T cells potentially causing [[atopic dermatitis]].<ref name="pmid17320941"/> 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.<ref name="pmid19557146">{{cite journal | author = Demehri S, Morimoto M, Holtzman MJ, Kopan R | title = Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma | journal = PLoS Biol. | volume = 7 | issue = 5 | pages = e1000067 | year = 2009 | month = May | pmid = 19557146 | pmc = 2700555 | doi = 10.1371/journal.pbio.1000067 | laysummary = http://news.bbc.co.uk/2/hi/health/8055038.stm | laysource = BBC News }}</ref>

==References==
{{reflist | 2}}

==Further reading==
{{refbegin | 2}}
*{{cite journal | author=Ziegler SF, Liu YJ |title=Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. |journal=Nat. Immunol. |volume=7 |issue= 7 |pages= 709–14 |year= 2006 |pmid= 16785889 |doi= 10.1038/ni1360 }}
*{{cite journal | author=Liu YJ |title=Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation. |journal=J. Allergy Clin. Immunol. |volume=120 |issue= 2 |pages= 238–44; quiz 245–6 |year= 2007 |pmid= 17666213 |doi= 10.1016/j.jaci.2007.06.004 }}
*{{cite journal | author=Gilliet M, Soumelis V, Watanabe N, ''et al.'' |title=Human dendritic cells activated by TSLP and CD40L induce proallergic cytotoxic T cells. |journal=J. Exp. Med. |volume=197 |issue= 8 |pages= 1059–63 |year= 2003 |pmid= 12707303 |doi= 10.1084/jem.20030240 }}
*{{cite journal | author=Watanabe N, Hanabuchi S, Marloie-Provost MA, ''et al.'' |title=Human TSLP promotes CD40 ligand-induced IL-12 production by myeloid dendritic cells but maintains their Th2 priming potential. |journal=Blood |volume=105 |issue= 12 |pages= 4749–51 |year= 2005 |pmid= 15741223 |doi= 10.1182/blood-2004-09-3622 }}
*{{cite journal | author=Lee HC, Ziegler SF |title=Inducible expression of the proallergic cytokine thymic stromal lymphopoietin in airway epithelial cells is controlled by NFkappaB. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=104 |issue= 3 |pages= 914–9 |year= 2007 |pmid= 17213320 |doi= 10.1073/pnas.0607305104 }}
*{{cite journal | author=Zhang K, Shan L, Rahman MS, ''et al.'' |title=Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease. |journal=Am. J. Physiol. Lung Cell Mol. Physiol. |volume=293 |issue= 2 |pages= L375–82 |year= 2007 |pmid= 17513456 |doi= 10.1152/ajplung.00045.2007 }}
*{{cite journal | author=Rochman I, Watanabe N, Arima K, ''et al.'' |title=Cutting edge: direct action of thymic stromal lymphopoietin on activated human CD4+ T cells. |journal=J. Immunol. |volume=178 |issue= 11 |pages= 6720–4 |year= 2007 |pmid= 17513717 |doi= }}
*{{cite journal | author=Wang YH, Angkasekwinai P, Lu N, ''et al.'' |title=IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. |journal=J. Exp. Med. |volume=204 |issue= 8 |pages= 1837–47 |year= 2007 |pmid= 17635955 |doi= 10.1084/jem.20070406 |pmc=2118667}}
{{refend}}

[[Category:Immunology]]

Versione delle 21:00, 18 dic 2012

TSLP (Thymic Stromal Lymphopoietin) è una citochina prodotta da cellule epiteliali timiche presenti nei corpuscoli di Hassal.



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 is produced mainly by non-hematopoietic cells such as fibroblasts, epithelial cells and different types of stromal or stromal-like cells.[senza fonte] 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.[1][2] Alternative splicing of this gene results in two transcript variants.[2]

Function

It mainly impacts myeloid cells and induces the release of T cell-attracting chemokines from monocytes [senza fonte] and enhances the maturation of myeloid (CD11c+) dendritic cells.[3] TSLP has also been shown to activate maturation of specific subset of dendritic cells located within the epidermis, Langerhans cell.[4] Within the thymus TSLP activation of both myeloid and plasmacytoid (CD123+) dendritic cells results in the production of regulatory T cells.[5][6]

Signalling

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

Disease

TSLP expression is linked to many disease states including asthma,[8] inflammatory arthritis,[9] atopic dermatitis,[4] and eczema and other allergic states.[10][11] 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 orientate the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway).[senza fonte] The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways [senza fonte].

Inflammatory arthritis

Atopic Dermatitis

TSLP-activated Langerhan cells of the epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis.[4] 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.[12]

References

  1. ^ Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD, Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation, in Leukemia, vol. 15, n. 8, Aug 2001, pp. 1286–92, DOI:10.1038/sj.leu.2402175.
  2. ^ a b Entrez Gene: TSLP thymic stromal lymphopoietin, su ncbi.nlm.nih.gov.
  3. ^ Reche PA, Soumelis V, Gorman DM, et al., Human thymic stromal lymphopoietin preferentially stimulates myeloid cells, in J. Immunol., vol. 167, n. 1, July 2001, pp. 336–43.
  4. ^ a b c Ebner S, Nguyen VA, Forstner M, Wang YH, Wolfram D, Liu YJ, Romani N, Thymic stromal lymphopoietin converts human epidermal Langerhans cells into antigen-presenting cells that induce proallergic T cells, in J. Allergy Clin. Immunol., vol. 119, n. 4, April 2007, pp. 982–90, DOI:10.1016/j.jaci.2007.01.003.
  5. ^ Watanabe N, Wang YH, Lee HK, Ito T, Wang YH, Cao W, Liu YJ, Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus, in Nature, vol. 436, n. 7054, August 2005, pp. 1181–5, DOI:10.1038/nature03886.
  6. ^ Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, Arima K, Wang YH, Voo KS, Cao W, Liu YJ, Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus, in J. Immunol., vol. 184, n. 6, March 2010, pp. 2999–3007, DOI:10.4049/jimmunol.0804106.
  7. ^ Isaksen DE, Baumann H, Trobridge PA, Farr AG, Levin SD, Ziegler SF, Requirement for stat5 in thymic stromal lymphopoietin-mediated signal transduction, in J. Immunol., vol. 163, n. 11, December 1999, pp. 5971–7.
  8. ^ Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, Robinson D, Zhang G, Zhao J, Lee TH, Corrigan C, Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity, in J. Immunol., vol. 174, n. 12, June 2005, pp. 8183–90.
  9. ^ 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, A possible role for TSLP in inflammatory arthritis, in Biochem. Biophys. Res. Commun., vol. 357, n. 1, May 2007, pp. 99–104, DOI:10.1016/j.bbrc.2007.03.081.
  10. ^ Soumelis V, Liu YJ, Human thymic stromal lymphopoietin: a novel epithelial cell-derived cytokine and a potential key player in the induction of allergic inflammation, in Springer Semin. Immunopathol., vol. 25, n. 3-4, February 2004, pp. 325–33, DOI:10.1007/s00281-003-0152-0.
  11. ^ 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, Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP, in Nat. Immunol., vol. 3, n. 7, July 2002, pp. 673–80, DOI:10.1038/ni805.
  12. ^ Demehri S, Morimoto M, Holtzman MJ, Kopan R, Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma, in PLoS Biol., vol. 7, n. 5, May 2009, pp. e1000067, DOI:10.1371/journal.pbio.1000067.

Further reading

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