TLR 4
Encyclopedia
Toll-like receptor 4 is a protein
that in humans is encoded by the TLR4 gene
. TLR 4 is a toll-like receptor
. It detects lipopolysaccharide
from Gram-negative
bacteria
and is thus important in the activation of the innate immune system
. TLR4 has also been designated as CD284 (cluster of differentiation
284).
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila
to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta
, and in myelomonocytic subpopulation of the leukocytes. It has been implicated in signal transduction
events induced by lipopolysaccharide
(LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Also, several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.
with TOLLIP
, Myd88
and Lymphocyte antigen 96
. Researchers from NTNU has described how intracellular trafficking of TLR4 is dependent on the GTPase Rab-11a
, and knock down of Rab-11a results in hampered TLR4 recruitment to E. coli-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway
. A recent study http://www.sciencedaily.com/releases/2011/02/110228151911.htm has suggested a link between the TLR 4 receptor and binge drinking
; when researchers manipulated the genes responsible for the expression of TLR 4 and GABA
receptors in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours.
Toll-like receptor 4 has also been shown to be important for the long-term side-effects of opioid
analgesic
drugs. Various μ-opioid
receptor
ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as morphine
being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1
, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs, and in the emergence of side-effects such as hyperalgesia
and allodynia
that can become a problem following extended use of opioid drugs. Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects, and this has also been demonstrated with drugs that block TLR4 itself. Interestingly the response of TLR4 to opioid drugs has been found to be enantiomer
-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone
, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers. This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.) This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the TLR4 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. TLR 4 is a toll-like receptor
Toll-like receptor
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes...
. It detects lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
from Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and is thus important in the activation of the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
. TLR4 has also been designated as CD284 (cluster of differentiation
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
284).
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila
Drosophila
Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species to linger around overripe or rotting fruit...
to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, and in myelomonocytic subpopulation of the leukocytes. It has been implicated in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
events induced by lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
(LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Also, several transcript variants of this gene have been found, but the protein-coding potential of most of them is uncertain.
Interactions
TLR 4 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with TOLLIP
TOLLIP
Toll interacting protein, also known as TOLLIP, is an inhibitory adaptor protein that in humans is encoded by the TOLLIP gene.-Function:It is an inhibitory adaptor protein within Toll-like receptors...
, Myd88
Myd88
Myeloid differentiation primary response gene is a protein that, in humans, is encoded by the MYD88 gene.-Function:In mice, MyD88 is a universal adapter protein as it is used by all TLRs to activate the transcription factor NF-κB. Mal is necessary to recruit Myd88 to TLR 2 and TLR 4, and MyD88...
and Lymphocyte antigen 96
Lymphocyte antigen 96
Lymphocyte antigen 96 is a protein that in humans is encoded by the LY96 gene.The protein encoded by this gene is involved in binding lipopolysaccharide with TLR 4. It is also known as "MD2".-Interactions:...
. Researchers from NTNU has described how intracellular trafficking of TLR4 is dependent on the GTPase Rab-11a
RAB11A
Ras-related protein Rab-11A is a protein that in humans is encoded by the RAB11A gene.-Interactions:RAB11A has been shown to interact with RAB11FIP2, RAB11FIP4, RAB11FIP1, RAB11FIP5 and RAB11FIP3....
, and knock down of Rab-11a results in hampered TLR4 recruitment to E. coli-containing phagosomes and subsequent reduced signal transduction through the MyD88-independent pathway
. A recent study http://www.sciencedaily.com/releases/2011/02/110228151911.htm has suggested a link between the TLR 4 receptor and binge drinking
Binge drinking
Binge drinking or heavy episodic drinking is the modern epithet for drinking alcoholic beverages with the primary intention of becoming intoxicated by heavy consumption of alcohol over a short period of time. It is a kind of purposeful drinking style that is popular in several countries worldwide,...
; when researchers manipulated the genes responsible for the expression of TLR 4 and GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
receptors in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours.
Toll-like receptor 4 has also been shown to be important for the long-term side-effects of opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
drugs. Various μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
ligands have been tested and found to also possess action as agonists or antagonists of TLR4, with opioid agonists such as morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
being TLR4 agonists, while opioid antagonists such as naloxone were found to be TLR4 antagonists. Activation of TLR4 leads to downstream release of inflammatory modulators including TNF-α and Interleukin-1
IL1B
Interleukin-1 beta also known as catabolin, is a cytokine protein that in humans is encoded by the IL1B gene. IL-1β precursor is cleaved by caspase 1 . Cytosolic thiol protease cleaves the product to form mature IL-1β.- Function :Interleukin 1 was discovered by Gery in 1972...
, and constant low-level release of these modulators is thought to reduce the efficacy of opioid drug treatment with time, and be involved in both the development of tolerance to opioid analgesic drugs, and in the emergence of side-effects such as hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
and allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
that can become a problem following extended use of opioid drugs. Drugs that block the action of TNF-α or IL-1β have been shown to increase the analgesic effects of opioids and reduce the development of tolerance and other side-effects, and this has also been demonstrated with drugs that block TLR4 itself. Interestingly the response of TLR4 to opioid drugs has been found to be enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
, which lack affinity for opioid receptors, still produce the same activity at TLR4 as their "normal" enantiomers. This means that the unnatural enantiomers of opioid antagonists, such as (+)-naloxone, can be used to block the TLR4 activity of opioid analgesic drugs, while leaving the μ-opioid receptor mediated analgesic activity unaffected.) This may also be the mechanism behind the beneficial effect of ultra-low dose naltrexone on opioid analgesia.
Agonists
- Morphine-3-glucuronideMorphine-3-glucuronideMorphine-3-glucuronide is a metabolite of morphine produced by UGT2B7. It is not active as an opioid agonist, but does have some action as a convulsant, which does not appear to be mediated through opioid receptors; it is mediated by GABA/glycinergic system...
(inactive at opioid receptors, so selective for TLR4 activation) - MorphineMorphineMorphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
- OxycodoneOxycodoneOxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
- LevorphanolLevorphanolLevorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...
- PethidinePethidinePethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
- Fentanyl
- MethadoneMethadoneMethadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
- BuprenorphineBuprenorphineBuprenorphine is a semi-synthetic opioid that is used...
- "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity, although (+)-morphine also shows activity as a sigma receptorSigma receptorThe sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
agonist. - LPS
Antagonists
- The lipid ALipid ALipid A is a lipid component of an endotoxin held responsible for toxicity of Gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane...
analog eritoranEritoranEritoran is an investigational drug for the treatment of severe sepsis, an excessive inflammatory response to an infection. It is being developed by Eisai Co. and administered intravenously as eritoran tetrasodium. , a Phase III clinical trial is recruiting patients.-Mechanism of action:Toll-like...
acts as a TLR4 antagonist. , it is being developed as a drug against severe sepsisSepsisSepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
. - NaloxoneNaloxoneNaloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...
- NaltrexoneNaltrexoneNaltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...
- (+)-naloxone(+)-Naloxone-Naloxone is a drug which is the "unnatural" enantiomer of the opioid antagonist drug -naloxone. Unlike "normal" naloxone, -naloxone has no significant affinity for opioid receptors, but instead has been discovered to act as a selective antagonist of Toll-like receptor 4...
("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition) - (+)-naltrexone
- LPS-RS
- IbudilastIbudilastIbudilast is an antiinflammatory drug used mainly in Japan, which acts as a phosphodiesterase inhibitor, inhibiting the PDE-4 subtype to the greatest extent, but also showing significant inhibition of other PDE subtypes.Ibudilast has bronchodilator, vasodilator and neuroprotective effects, and is...
- PropentofyllinePropentofyllinePropentofylline is a xanthine derivative with purported neuroprotective effects.-Pharmacology:It is a phosphodiesterase inhibitor.It also acts as an adenosine reuptake inhibitor.-Uses:...
- AmitriptylineAmitriptylineAmitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...