TSLP was initially observed to have both pro-inflammatory and anti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the two transcript variants, with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory.[5][13]
As mentioned, TSLP serves as an alarmin following TLR binding by certain pathogen-associated molecular patterns (PAMPs), including viral and bacterial ones, rather than just irritation by allergens. Thus, TSLP also plays an early role in the initiation of type 1 and 3 immune responses to pathogens. This activity has thus far been best described in the respiratory mucosa.[19]
TSLP-activated CD11b+ DCs can promote the proliferation and long-term survival of CD8+ cytotoxic T cells, promoting the development of lasting adaptive cellular immunity. Analogously, TSLP-activated CD11c+ cells are essential for the development of IgA antibodies following pneumococcal infection. TSLP also holds considerable promise as a novel vaccine adjuvant and anti-cancer immunotherapy due to its broad and potent alarmin functionality, as is evidenced by numerous animal studies.[19]
TSLP expression is linked to many disease states including asthma,[24] inflammatory arthritis,[25] atopic dermatitis,[26] eczema, eosinophilic esophagitis and other allergic states.[27][28] The factors inducing the activation of TSLP release are not clearly defined.
Asthmaedit
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]
Atopic dermatitisedit
TSLP-activated Langerhans cells of the epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis.[26] It is thought that by 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.[29]
Therapeutic targetingedit
The TSLP signaling axis is an attractive therapeutic target. Amgen's Tezepelumab, a monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma.[30][31] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed.[22] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface,[32] natural products [33] and computational fragment-based screening.[34]
Referencesedit
^ abcGRCh38: Ensembl release 89: ENSG00000145777 – Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000024379 – Ensembl, May 2017
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^ abcHarada M, Hirota T, Jodo AI, Doi S, Kameda M, Fujita K, et al. (March 2009). "Functional analysis of the thymic stromal lymphopoietin variants in human bronchial epithelial cells". American Journal of Respiratory Cell and Molecular Biology. 40 (3): 368–374. doi:10.1165/rcmb.2008-0041OC. PMID 18787178.
^Friend SL, Hosier S, Nelson A, Foxworthe D, Williams DE, Farr A (March 1994). "A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells". Experimental Hematology. 22 (3): 321–328. PMID 8112430.
^ abFornasa G, Tsilingiri K, Caprioli F, Botti F, Mapelli M, Meller S, et al. (August 2015). "Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin". The Journal of Allergy and Clinical Immunology. 136 (2): 413–422. doi:10.1016/j.jaci.2015.04.011. PMC4534776. PMID 26014813.
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^Smolinska S, Antolín-Amérigo D, Popescu FD, Jutel M (August 2023). "Thymic Stromal Lymphopoietin (TSLP), Its Isoforms and the Interplay with the Epithelium in Allergy and Asthma". International Journal of Molecular Sciences. 24 (16): 12725. doi:10.3390/ijms241612725. PMC10454039. PMID 37628907.
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^ abCao L, Qian W, Li W, Ma Z, Xie S (2023-09-22). "Type III interferon exerts thymic stromal lymphopoietin in mediating adaptive antiviral immune response". Frontiers in Immunology. 14: 1250541. doi:10.3389/fimmu.2023.1250541. PMC10556530. PMID 37809098.
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^ abEbner 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". The Journal of Allergy and Clinical Immunology. 119 (4): 982–990. doi:10.1016/j.jaci.2007.01.003. PMID 17320941.
^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 Seminars in Immunopathology. 25 (3–4): 325–333. doi:10.1007/s00281-003-0152-0. PMID 14999427. S2CID 9713181.
^Demehri S, Morimoto M, Holtzman MJ, Kopan R (May 2009). "Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma". PLOS Biology. 7 (5): e1000067. doi:10.1371/journal.pbio.1000067. PMC2700555. PMID 19557146.
Lay summary in: "Eczema's link to asthma uncovered". BBC News. 24 May 2009.
^"Tezspire- tezepelumab-ekko injection, solution". DailyMed. Retrieved 24 December 2021.
^"Tezspire (tezepelumab) approved in the US for severe asthma". AstraZeneca (Press release). 17 December 2021. Retrieved 17 December 2021.
^Park S, Park Y, Son SH, Lee K, Jung YW, Lee KY, et al. (October 2017). "Synthesis and biological evaluation of peptide-derived TSLP inhibitors". Bioorganic & Medicinal Chemistry Letters. 27 (20): 4710–4713. doi:10.1016/j.bmcl.2017.09.010. PMID 28927768.
^Park BB, Choi JW, Park D, Choi D, Paek J, Kim HJ, et al. (June 2019). "Structure-Activity Relationships of Baicalein and its Analogs as Novel TSLP Inhibitors". Scientific Reports. 9 (1): 8762. Bibcode:2019NatSR...9.8762P. doi:10.1038/s41598-019-44853-5. PMC6584507. PMID 31217492.
^Van Rompaey D, Verstraete K, Peelman F, Savvides SN, Augustyns K, Van Der Veken P, De Winter H (December 2017). "Virtual screening for inhibitors of the human TSLP:TSLPR interaction". Scientific Reports. 7 (1): 17211. Bibcode:2017NatSR...717211V. doi:10.1038/s41598-017-17620-7. PMC5722893. PMID 29222519.
External linksedit
Overview of all the structural information available in the PDB for UniProt: Q969D9 (Thymic stromal lymphopoietin) at the PDBe-KB.