Toll-like family

Overview: Toll-like receptors are single TM cell-surface proteins with multiple leucine-rich regions in the extracellular portion, which participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular protein kinases and regulation of gene transcription. As well as responding to exogenous infectious agents, it has been suggested that selected members of the family may be activated by endogenous ligands, such as hsp60 (Ohashi et al., 2000).

Nomenclature	Other names	Ensembl ID	Selective agonists
TLR2	CD282	ENSG00000137462	Peptidoglycan (Schwandner et al., 1999; Yoshimura et al., 1999)
TLR3	CD283	ENSG00000164342	PolyIC (Alexopoulou et al., 2001)
TLR4	CD284	ENSG00000136869	LPS (Poltorak et al., 1998), taxol (Kawasaki et al., 2000)
TLR5	–	ENSG00000187554	Flagellin (Hayashi et al., 2001)
TLR7	–	ENSG00000196664	R848 (Hemmi et al., 2002), imiquimod (Hemmi et al., 2002)
TLR8	–	ENSG00000101916	R848 (Hemmi et al., 2002), imiquimod
TLR9	CD289	ENSG00000173366	CpG (Hemmi et al., 2000)

Members of the family appear to interact in the recognition of many ligands such that the potency of ligands is altered with different combination patterns (e.g. TLR1/2 and TLR2/6, Takeuchi et al., 2001; 2002;).

Further members of the family, which includes TLR1 (Toll/interleukin-1 receptor-like protein, CD281, ENSG00000174125), TLR6 (ENSG00000174130), TLR10 (ENSG00000174123) and TLR11 (ENSMUSG00000051969), have been less well characterised.

Glossary

Abbreviations:

CpG

DNA enriched in cytosine : guanosine pairs

imiquimod

1-(4-amino-imidazo[4,5-c]quinolin-1-yl)-2-methylpropane, also known as R837

LPS

lipopolysaccharide derived from Gram-negative bacteria

polyIC

polyinosine-polycytosine

R848

1-(4-amino-2-ethoxymethyl-imidazo[4,5-c]quinolin-1-yl)-2-methyl-propan-2-ol, also known as resiquimod and S28463

Further Reading

Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S et al. (2006). Genetic analysis of host resistance: toll-like receptor signaling and immunity at large. Annu Rev Immunol24: 353–389.

Celis E (2007). Toll-like receptor ligands energize peptide vaccines through multiple paths. Cancer Res67: 7945–7947.

Chao W (2009). Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart. Am J Physiol Heart Circ Physiol296: H1–H12.

Doyle SL, O'Neill LA (2006). Toll-like receptors: from the discovery of NFκB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol72: 1102–1113.

Ehlers M, Ravetch JV (2007). Opposing effects of Toll-like receptor stimulation induce autoimmunity or tolerance. Trends Immunol28: 74–79.

Feleszko W, Jaworska J, Hamelmann E (2006). Toll-like receptors–novel targets in allergic airway disease (probiotics, friends and relatives). Eur J Pharmacol533: 308–318.

Garantziotis S, Hollingsworth JW, Zaas AK, Schwartz DA (2008). The effect of toll-like receptors and toll-like receptor genetics in human disease. Annu Rev Med59: 343–359.

Gazzinelli RT, Denkers EY (2006). Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat Rev Immunol6: 895–906.

Hori M, Nishida K (2008). Toll-like receptor signaling: defensive or offensive for the heart? Circ Res102: 137–139.

Kanzler H, Barrat FJ, Hessel EM, Coffman RL (2007). Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med13: 552–559.

Konat GW, Kielian T, Marriott I (2006). The role of Toll-like receptors in CNS response to microbial challenge. J Neurochem99: 1–12.

Krieg AM (2006). Therapeutic potential of Toll-like receptor 9 activation. Nat Rev Drug Discovery5: 471–484.

Li H, Sun B (2007). Toll-like receptor 4 in atherosclerosis. J Cell Mol Med11: 88–95.

Marsh BJ, Williams-Karnesky RL, Stenzel-Poore MP (2009). Toll-like receptor signaling in endogenous neuroprotection and stroke. Neuroscience158: 1007–1020.

Marshak-Rothstein A, Rifkin IR (2007). Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu Rev Immunol25: 419–441.

Miggin SM, O'Neill LA (2006). New insights into the regulation of TLR signaling. J Leukoc Biol80: 220–226.

O'Neill LA, Bowie AG (2007). The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol7: 353–364.

Sabroe I, Parker LC, Dower SK, Whyte MK (2008). The role of TLR activation in inflammation. J Pathol214: 126–135.

Sutmuller RP, Morgan ME, Netea MG, Grauer O, Adema GJ (2006). Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol27: 387–393.

Trinchieri G, Sher A (2007). Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol7: 179–190.

Wenzel J, Tormo D, Tuting T (2008). Toll-like receptor-agonists in the treatment of skin cancer: history, current developments and future prospects. Handb Exp Pharmacol : 201–220.