Thymic stromal lymphopoietin

Last updated
TSLP
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TSLP , thymic stromal lymphopoietin
External IDs OMIM: 607003 MGI: 1855696 HomoloGene: 81957 GeneCards: TSLP
Gene location (Human)
Ideogram human chromosome 5.svg
Chr. Chromosome 5 (human) [1]
Human chromosome 5 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 5q22.1Start111,070,062 bp [1]
End111,078,026 bp [1]
Orthologs
SpeciesHumanMouse
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

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.

Contents

TSLP is produced mainly by non-hematopoietic cells such as fibroblasts, epithelial cells and different types of stromal or stromal-like cells.[ citation needed ] 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 [ citation needed ] 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).[ 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. [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]

Inhibition

The TSLP signaling axis is an attractive therapeutic target. Amgen's Tezepelumab, a monoclonal antibody which blocks TSLP, is currently in phase III clinical trials for the treatment of asthma. [17] Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed. [18] Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface, [19] natural products [20] and computational fragment-based screening. [21]

Related Research Articles

Dendritic cell specialized cells of the hematopoietic system with branch-like extensions

Dendritic cells (DCs) are antigen-presenting cells of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.

Interleukin 33 IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines.

Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.

Interleukin 25 Cytokine that belongs to the IL-17 cytokine family

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E) – is a protein that in humans is encoded by the IL25 gene on chromosome 14. IL-25 was discovered in 2001 and is made up of 177 amino acids.

Interleukin 17 Inerleukin 17 protein family containing interleukins 17A, 17B, 17C, 17D, 17E and 17F

Interleukin 17A is a pro-inflammatory cytokine. This cytokine is produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17 transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17 protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17 is often referred to as CTLA8.

CD80 mammalian protein found in Homo sapiens

Cluster of differentiation 80 is a B7, type I membrane protein that is in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is closely related to CD86, another B7 protein (B7-2), and often works in tandem, binding to the same receptors to prime T cells.

CD86 mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein expressed on dendritic cells, macrophages, B-cells, and other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T-cell activation and survival. Depending on the ligand bound, CD86 can be used to signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

CCL18 mammalian protein found in Homo sapiens

Chemokine ligand 18 (CCL18) is a small cytokine belonging to the CC chemokine family. The functions of CCL18 have been well studied in laboratory settings, however the physiological effects of the molecule in living organisms have been difficult to characterize because there is no similar protein in rodents that can be studied. The receptor for CCL18 has been identified in humans only recently, which will help scientists understand the molecule's role in the body.

OX40L is the ligand for OX40 and is stably expressed on many antigen-presenting cells such as DC2s, macrophages, and activated B lymphocytes.

TLR6 protein-coding gene in the species Homo sapiens

Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 is a transmembrane protein, member of toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. TLR6 acts in a heterodimer form with toll-like receptor 2 (TLR2). Its ligands include multiple diacyl lipopeptides derived from gram-positive bacteria and mycoplasma and several fungal cell wall saccharides. After dimerizing with TLR2, the NF-κB intracellular signalling pathway is activated, leading to an pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286.

C-C chemokine receptor type 7 protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21).

LIGHT (protein) protein-coding gene in the species Homo sapiens

LIGHT, also known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily. It is recognized by herpesvirus entry mediator (HVEM), as well as decoy receptor 3.

TNFSF12 protein-coding gene in the species Homo sapiens

Tumor necrosis factor ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK) is a protein that in humans is encoded by the TNFSF12 gene.

ICOSLG protein-coding gene in the species Homo sapiens

ICOS ligand is a protein that in humans is encoded by the ICOSLG gene. ICOSLG has also been designated as CD275.

TREM1 protein-coding gene in the species Homo sapiens

Triggering receptor expressed on myeloid cells 1 is a protein that in humans is encoded by the TREM1 gene.

KLRB1 protein-coding gene in the species Homo sapiens

Killer cell lectin-like receptor subfamily B, member 1, also known as NK1.1, KLRB1, NKR-P1A or CD161, is a human gene.

CRLF2 protein-coding gene in the species Homo sapiens

Cytokine receptor-like factor 2 is a protein that in humans is encoded by the CRLF2 gene. It forms a ternary signaling complex with TSLP and interleukin-7 receptor-α, capable of stimulating cell proliferation through activation of STAT3, STAT5 and JAK2 pathways and is implicated in the development of the hematopoietic system. Rearrangement of this gene with immunoglobulin heavy chain gene (IGH), or with P2Y purinoceptor 8 gene (P2RY8) is associated with B-progenitor- and Down syndrome- acute lymphoblastic leukemia (ALL).

Interleukin-7 receptor-α protein-coding gene in the species Homo sapiens

Interleukin-7 receptor subunit alpha (IL7R-α) also known as CD127 is a protein that in humans is encoded by the IL7R gene.

Interleukin 23 heterodimeric cytokine acting as mediator of inflammation

Interleukin-23 (IL-23) is a heterodimeric cytokine composed of an IL12B (IL-12p40) subunit and the IL23A (IL-23p19) subunit. IL-23 is part of IL-12 family of cytokines. A functional receptor for IL-23 has been identified and is composed of IL-12R β1 and IL-23R. Adnectin-2 is binding to IL-23 and compete with IL-23/IL-23R. mRNA of IL-23R is 2,8 kB in length and includes 12 exons. The translated protein contains 629 amino acids, which is a type I penetrating protein includes signal peptide, an N-terminal fibronectin III-like domain and an intracellular part contains 3 potential tyrosine phosphorylation domains. There are 24 variants of splicing of IL-23R in mitogen-activated lymphocytes. IL-23R has some single nucleotide polymorphisms in the domain of binding IL-23 so there can be differences in activation of Th17. There is also variant of IL-23R which has just extracellular part and it´s known as soluble IL-23R. This form can compete with membrane form to bind IL-23 and there can be difference in activation of Th17 immune response and regulation of inflammation and immune function.

In cell biology, TH9 cells are a sub-population of CD4+T cells that produce interleukin-9 (IL-9). They play a role in defense against helminth infections, in allergic responses, in autoimmunity, and tumor suppression.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145777 - Ensembl, May 2017
  2. 1 2 3 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 (August 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. 1 2 "Entrez Gene: TSLP thymic stromal lymphopoietin".
  7. ↑ Reche PA, Soumelis V, Gorman DM, Clifford T, Travis M, Zurawski SM, et al. (July 2001). "Human thymic stromal lymphopoietin preferentially stimulates myeloid cells". Journal of Immunology. 167 (1): 336–43. doi: 10.4049/jimmunol.167.1.336 . PMID   11418668.
  8. 1 2 3 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". The Journal of Allergy and Clinical Immunology. 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, et al. (March 2010). "Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus". Journal of Immunology. 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". Journal of Immunology. 163 (11): 5971–7. PMID   10570284.
  12. ↑ Ying S, O'Connor B, Ratoff J, Meng Q, Mallett K, Cousins D, et al. (June 2005). "Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity". Journal of Immunology. 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, 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. 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 Seminars in Immunopathology. 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, et al. (July 2002). "Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP" (PDF). Nature Immunology. 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 Biology. 7 (5): e1000067. doi:10.1371/journal.pbio.1000067. PMC   2700555 . PMID   19557146. Lay summary –BBC News.
  17. ↑ "Studies found for: Tezepelumab". ClinicalTrials.Gov. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services.
  18. ↑ Verstraete K, Peelman F, Braun H, Lopez J, Van Rompaey D, Dansercoer A, et al. (April 2017). "Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma". Nature Communications. 8: 14937. doi:10.1038/ncomms14937. PMC   5382266 . PMID   28368013.
  19. ↑ 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.
  20. ↑ 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. doi:10.1038/s41598-019-44853-5. PMC   6584507 . PMID   31217492.
  21. ↑ 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. doi:10.1038/s41598-017-17620-7. PMC   5722893 . PMID   29222519.

Further reading

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