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.
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]
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.[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 targeting
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]
^Quentmeier H, Drexler HG, Fleckenstein D, Zaborski M, Armstrong A, Sims JE, Lyman SD (August 2001). "Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation". Leukemia. 15 (8): 1286–1292.
doi:
10.1038/sj.leu.2402175.
PMID11480573.
S2CID12658276.
^
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.
PMID18787178.
^Saluja R, Zoltowska A, Ketelaar ME, Nilsson G (May 2016). "IL-33 and Thymic Stromal Lymphopoietin in mast cell functions". European Journal of Pharmacology. Pharmacological modulation of Mast cells and Basophils. 778: 68–76.
doi:
10.1016/j.ejphar.2015.04.047.
PMID26051792.
^Koyama K, Ozawa T, Hatsushika K, Ando T, Takano S, Wako M, et al. (May 2007). "A possible role for TSLP in inflammatory arthritis". Biochemical and Biophysical Research Communications. 357 (1): 99–104.
doi:
10.1016/j.bbrc.2007.03.081.
PMID17416344.
^
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.
PMID17320941.
^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.
PMID14999427.
S2CID9713181.
^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.
PMID28927768.