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 production has been observed in various species, including humans and mice. In humans TSLP is encoded by the TSLPgene.[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[citation needed] and enhances the maturation of myeloid (CD11c+) dendritic cells.[3] TSLP has also been shown to activate the maturation of a specific subset of dendritic cells located within the epidermis, called Langerhans cells.[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 CRLF2 and the IL-7R alpha chain. After binding STAT5 phosphorylation is induced resulting in the expression of upstream transcription factors.[7]
Disease
TSLP expression is linked to many disease states including asthma,[8] inflammatory arthritis,[9] atopic dermatitis,[4] eczema, eosinophilic esophagitis 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 orient the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway).[citation needed] The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways [citation needed].
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.[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
↑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. PMID11480573.
↑ 4.04.14.2Ebner 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. PMID17320941.
↑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. PMID16121185.
↑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. PMID10570284.
↑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. PMID15944327.
↑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. PMID17416344.
↑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. PMID14999427.
↑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". Nat. Immunol. 3 (7): 673–80. doi:10.1038/ni805. PMID12055625.
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. PMID16785889.
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. PMID17666213.
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. PMID17513456.
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. PMID17513717.