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Cytokine Receptors (Interleukin-1 Receptor/TIR Family)

The interleukin-1/TIR family in animals comprises three subgroups of proteins; of these, two are type I integral membrane receptor proteins and the third is a group of intracellular proteins. All family members are characterized by the presence of a domain of ca. 200 amino residues referred to as the TIR (toll – interleukin-1 resistance) domain. Detailed sequence comparisons of a large number of TIR domains have revealed the presence of three conserved regions among the different members of the family; box 1 (FDAFISY), box 2 (GYKLC-RD-PG), and box 3 (a conserved W surrounded by basic residues). Crystal structures of the TIR domains of human TLR-1 and TLR-2 revealed that the domain is a compact globular structure composed of a series of α helices surrounding a core of β strands. Box 1 and 2 lie close together in space and form a composite site with box 2 projecting as a loop from the domain. Box 3 forms the core of the long C-terminal α helix. This suggests that these three sequences may have been conserved because they are important for protein-protein interactions rather than for the overall structural stability of the domain.

In the IL-1 receptor-like subfamily, the TIR domain is C-terminal to a single transmembrane sequence and the N-terminal region of the protein is composed of three immunoglobulin-like regions. The N-terminal region is extracellular, is composed of either one (SIGGR) or three immunoglobulin domains and binds ligands. In the TLR (toll-like receptor) subfamily, the TIR domain is C-terminal to a single transmembrane sequence. The N-terminal region is extracellular, is composed of a variable number of leucine rich repeats that form a large flat, but concave surface that appears capable of accommodating a wide range of ligand structures. The third subfamily, not tabulated here because they are not receptors, are intracellular protein adaptors containing minimally one TIR domain, usually linked to one or more other protein interaction domains such as a death domain. The prototype for this group of proteins is myD88 that binds to the site on the receptor TIR domains formed by Box-1 and 2, via a homotypic TIR-TIR interaction, and couples the receptors to downstream signaling mechanisms.

The IL-1 receptor-like subfamily of receptors are conventional polypeptide hormone receptors for cytokines of the IL-1 family (IL-1α (IL-1F1), IL-1βα (IL-1F2), IL-1ra α (IL-1F3), IL-18 (IL-1F4) and IL-1F5-10). The ligand receptor pairings for IL-1F1-4 are well defined and supported by good receptor pharmacology. However, while receptor-selective, functional effects have been found for several other IL-1Fs, high affinity receptor binding has not been detected. The well characterized functional receptors (IL-1R and IL-18R) are heterodimers (IL-1R/IL-1AcP and IL-18R/IL-1RAcPL) and it is possible therefore that the low affinity of binding so far detected is due to lack of the appropriate heterodimers.

The finding that tolls were the long sought after receptors for bacterial agonists such as gram negative LPS was triggered by the break through observation that flies conditionally mutated in the toll-1 gene, a gene known only to have a role in embryonic development prior to that time, became uniquely sensitive to fungal infection when subject to gene inactivation as adults. Subsequent to that observation large amount of literature documented the role played by animal TLRs as receptors for a wide range of bacterial and viral products, broadly termed pathogen associated molecular patterns (PAMPs). This recent and rapidly moving field is still, unsurprisingly, full of gaps. Thus, there are few convincing radioligand binding studies for any TLR/ligand pair with most data on specificity being derived from functional studies. In addition, there is increasing evidence that most TLRs function in the context of multi-component complexes at the cell surface, with many diverse proteins present, well characterized examples being the TLR1/TLR2/CD14 or TLR6/TLR2/CD14 complexes that mediate responses to lipotechoic acid.

 

The Tables below contain accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Cytokines - Interleukin-1 Receptor/TIR Family (a)

Receptor Type I IL-1 Receptor (I0654)    Type II IL-1 Receptor
ST2 IL-18 Receptor IL-1Rrp2
Currently Accepted Name IL-1RI IL-1RII ST2 IL-18 Receptor IL-1Rrp2
Alternative Name     T2
Fit-1
IL-1 R7  
Subunit Composition IL1RI/IL1R AcP IL1RII ST2 IL18R/IL18RAcP IL1Rrp2/IL1RAcP
Selective Agonistsb IL-1α (I2778)
IL-1β (I9401)
None, receptor does not signal Not Known
IL-18 (I0531(r)) IL-F6
IL1F8
IL1F9
Selective Antagonists IL-1ra Not applicable Not Known
Not Known
Not Known
Signal Transduction Mechanisms SAPKs
NFκB
SAPKs
NFκB
SAPKs
NFκB
SAPKs
NFκB
SAPKs
NFκB
Radioligands of Choice [125I]-IL-1α
[125I]-IL-1β
[125I]-IL-1ra
[125I]-IL-1α
[125I]-IL-1β
[125I]-ST2 binding protein [125I]-IL-18 Not Known
Tissue Expression All tissues Leukocytes Leukocytes Lymphocytes Epithelia
Physiological Function Host defense Host defense Not Known
T cell regulation Inflammation
Disease Relevance Inflammation Inflammation Not Known
Autoimmunity Inflammation

 

Receptor TIGIRR-1 TIGIRR-2 IL-1RAcP SIGIRR IL-18RAcP
Currently Accepted Name TIGIRR-1 TIGIRR-2 IL-1RAcP SIGIRR IL-18RAcP
Alternative Name IL-1R9 OP4
IL1RAPL
     
Subunit Composition TIGIRR -1 Not Known
IL1RI/IL1R AcP Not Known
IL18R/IL18RAcP
Selective Agonistsb Not Known
Not Known
IL-1α (I2778)
IL-1β (I9401)
Not Known
IL-18
Selective Antagonists Not Known
Not Known
IL-1ra Not Known
Not Known
Signal Transduction
Mechanisms
Not Known
Not Known
SAPKs
NFκB
Not Known
SAPKs
NFκB
Radioligands of Choice Not Known
Not Known
[125I]-IL-1α
[125I]-IL-1β
[125I]-IL-1ra
Not Known [125I]-IL-18
Tissue Expression Brain, muscle, placenta Widespread All tissues Epithelial Lymphocytes
Physiological Function Not Known
Not Known
Host defense TIR signaling inhibitor T cell regulation
Disease Relevance Not Known
Mental retardation Inflammation Inflammatory bowel disease Autoimmunity
Allergy

 

 

Cytokines - Interleukin-1 Receptor/TIR Family (c)

Receptor TLR-1 TLR -2 TLR -3 TLR -4 TLR -5
Currently Accepted Name Toll-1 Toll-2 Toll-3 Toll-4 Toll-5
Alternative Name Toll-1
RSC786
Toll-2 Toll-3 Toll-4 Toll-5
Subunit Composition Toll-1/Toll-2/CD14 Toll-1/Toll-2/CD14 Not Known
(Tlr4)2CD14 Not Known
Selective Agonistsa Bacterial extracts
MD2
Bacterial extracts
MD2
dsRNA LPS (L3012, L4391)
(gram negative)
MD2
Flagellin
Selective Antagonists LTA
(L3265, L2515,
L4015, L3140)
LTA
(L3265, L2515,
L4015, L3140)
Not Known
Not Known
Not Known
Signal Transduction
Mechanisms
SAPKs
NFκB
SAPKs
NFκB
Not Known
SAPKs
NFκB
SAPKs
NFκB
Radioligands of Choice          
Tissue Expression Leukocytes Leukocytes Leukocytes Leukocytes Leukocytes
Physiological Function LTA receptor LTA receptor PAMP receptor LPS receptor PAMP receptor
Disease Relevance Lyme disease Infections Infections Meningitis Infections

 

Receptor TLR -6 TLR -7 TLR -8 TLR -9 TLR-10 TLR-11
Currently Accepted Name Toll-6 Toll-7 Toll-8 Toll-9 Toll-10 Toll-11
Alternative Name Toll-6 Toll-7 Toll-8 Toll-9 Toll-10 Toll-11
Subunit Composition Toll-6/Toll-2/CD14 Not Known
Not Known
Not Known
Not Known
Not Known
Selective Agonistsa Bacterial extracts
MD2
dsRNA CPG DNA Not Known
Not Known
Not Known
Selective Antagonists LTA
(L3265, L2515,
L4015, L3140)
R848 R848 CpG islands Not Known
Not Known
Signal Transduction
Mechanisms
Not Known
Not Known
SAPKs
NFκB
SAPKs
NFκB
SAPKs
NFκB
SAPKs
NFκB
Radioligands of Choice            
Tissue Expression Leukocytes Leukocytes Leukocytes Leukocytes Leukocytes Bladder
Physiological Function LTA receptor Not Known
Not Known
PAMP receptor PAMP receptor PAMP receptor
Disease Relevance Infections Infections Infections Infections Infections Urological infections

 

Footnotes

a) There are at least five Interleukin-1 like cytokines encoded in the human genome. These presumably are the ligands for the four orphan receptors that are IL-1R related (three Ig domains out/TIR domain cytoplasmic).

b) Product numbers refer to the human cytokine. For other species, please visit our website at www.sigmaaldrich.com and use our Product Search.

c) The Tolls have been found to be receptors for pathogen associated molecular patterns (PAMPs), such as that embodied in gram negative lipopolysaccharide. Reports have shown that Tolls can heterodimerize to form receptors, the specificity of which is created combinatorially. In addition, a small family of secreted cytokine-like molecules have been described, which may be the mammalian homologs of the fly spatzle proteins. However, to date, these have been found to be required for PAMP activation of Tolls rather than to be agonists when present alone. Finally, the Toll naming convention used here is for human Tolls.

 

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References