TLR8 | Toll-like receptor family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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TLR8

  Target has curated data in GtoImmuPdb

Target id: 1758

Nomenclature: TLR8

Family: Toll-like receptor family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1015 Xp22 TLR8 toll like receptor 8
Mouse - 1009 X 78.29 cM Tlr8 toll-like receptor 8
Rat - - X Tlr8 toll-like receptor 8
Previous and Unofficial Names
toll-like receptor 8 | CD288 | UNQ249/PRO286
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
CU-CPT8m Hs Inhibition 6.7 pKd 7
pKd 6.7 (Kd 2.2x10-7 M) [7]
Description: Dissociation constant measured using isothermal titration calorimetry (ITC) and the hTRL8 ectodomain.
CU-CPT8m Hs Inhibition 7.2 pIC50 7
pIC50 7.2 (IC50 6.7x10-8 M) [7]
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
motolimod Hs Agonist ~7.0 pEC50 4
pEC50 ~7.0 (EC50 ~1x10-7 M) [4]
3M-002 Hs Agonist 5.9 pEC50 5
pEC50 5.9 (EC50 1.32x10-6 M) [5]
Description: Assessed as ability to activate NF-κB in HEK293 cells expressing human TLR8.
compound 12p [Larson et al., 2017] Hs Agonist 5.3 pEC50 2
pEC50 5.3 (EC50 4.98x10-6 M) [2]
Immunopharmacology Comments
TLR8 is an endosomal receptor detecting ssRNA [6]. It may also bind synthetic imidazoquinoline anti-viral drugs. TLR8 signalling is reported to reprogramme the glycolytic metabolic profile of Treg cells, in a mechanism that blocks Treg-induced immunosuppression in the local microenvironment and that can re-activate effective Treg anti-tumour activity [3]. Additional evidence that demonstrates the potential role of TLR8 in immuno-oncology is reviewed in [1]
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 8 GO processes
GO:0002224 toll-like receptor signaling pathway TAS
GO:0006954 inflammatory response IBA
GO:0034158 toll-like receptor 8 signaling pathway IDA
GO:0034162 toll-like receptor 9 signaling pathway TAS
GO:0045087 innate immune response NAS
GO:0045089 positive regulation of innate immune response IDA
click arrow to show/hide IEA associations
GO:0001774 microglial cell activation IEA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0016064 immunoglobulin mediated immune response TAS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0016064 immunoglobulin mediated immune response TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 5 GO processes
GO:0002224 toll-like receptor signaling pathway TAS
GO:0034158 toll-like receptor 8 signaling pathway IDA
GO:0034162 toll-like receptor 9 signaling pathway TAS
GO:0045089 positive regulation of innate immune response IDA
click arrow to show/hide IEA associations
GO:0002755 MyD88-dependent toll-like receptor signaling pathway IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 7 GO processes
GO:0045078 positive regulation of interferon-gamma biosynthetic process IDA
GO:0045356 positive regulation of interferon-alpha biosynthetic process IDA
GO:0045359 positive regulation of interferon-beta biosynthetic process IDA
GO:0045416 positive regulation of interleukin-8 biosynthetic process IMP
GO:0050718 positive regulation of interleukin-1 beta secretion IDA
GO:2000778 positive regulation of interleukin-6 secretion IDA
GO:2001183 negative regulation of interleukin-12 secretion IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 5 GO processes
GO:0002224 toll-like receptor signaling pathway TAS
GO:0034158 toll-like receptor 8 signaling pathway IDA
GO:0034162 toll-like receptor 9 signaling pathway TAS
click arrow to show/hide IEA associations
GO:0001774 microglial cell activation IEA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Atherosclerosis susceptibility
Disease Ontology: DOID:1936
OMIM: 108725
Disease:  Crimean-Congo hemorrhagic fever
Disease Ontology: DOID:12287
Disease:  Fibrosis
Disease:  Mycobacterium tuberculosis, susceptibility to
Disease Ontology: DOID:399
OMIM: 607948

References

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1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. Larson P, Kucaba TA, Xiong Z, Olin M, Griffith TS, Ferguson DM. (2017) Design and Synthesis of N1-Modified Imidazoquinoline Agonists for Selective Activation of Toll-like Receptors 7 and 8. ACS Med. Chem. Lett., Epub ahead of print.

3. Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, Gao A, Huang L, Hsueh EC, Ford DA et al.. (2018) TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy. Cell Metabolism, Online Now. DOI: https://doi.org/10.1016/j.cmet.2018.09.020

4. Lu H, Dietsch GN, Matthews MA, Yang Y, Ghanekar S, Inokuma M, Suni M, Maino VC, Henderson KE, Howbert JJ et al.. (2012) VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin. Cancer Res., 18 (2): 499-509. [PMID:22128302]

5. Salunke DB, Yoo E, Shukla NM, Balakrishna R, Malladi SS, Serafin KJ, Day VW, Wang X, David SA. (2012) Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines. J. Med. Chem., 55 (18): 8137-51. [PMID:22924757]

6. Uematsu S, Akira S. (2008) Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol, (183): 1-20. [PMID:18071652]

7. Zhang S, Hu Z, Tanji H, Jiang S, Das N, Li J, Sakaniwa K, Jin J, Bian Y, Ohto U et al.. (2018) Small-molecule inhibition of TLR8 through stabilization of its resting state. Nat. Chem. Biol., 14 (1): 58-64. [PMID:29155428]

Contributors

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How to cite this page

Clare Bryant, Tom Monie.
Toll-like receptor family: TLR8. Last modified on 22/10/2018. Accessed on 16/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1758.