TLR4

Toll-like receptor 4 is a is_associated_with::protein that in humans is encoded by the TLR4 is_associated_with::gene. TLR 4 is a is_associated_with::toll-like receptor. It detects is_associated_with::lipopolysaccharide from is_associated_with::Gram-negative is_associated_with::bacteria and is thus important in the activation of the is_associated_with::innate immune system. TLR 4 has also been designated as CD284 (is_associated_with::cluster of differentiation 284). The molecular weight of TLR 4 is approximately 95 kDa.

Function
The protein encoded by this gene is a member of the is_associated_with::Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of is_associated_with::innate immunity. TLRs are highly conserved from is_associated_with::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 is_associated_with::cytokines necessary for the development of effective immunity.

The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in is_associated_with::placenta, and in is_associated_with::myelomonocytic subpopulation of the is_associated_with::leukocytes.

It cooperates with is_associated_with::LY96 (also referred as MD-2) and is_associated_with::CD14 to mediate in is_associated_with::signal transduction events induced by is_associated_with::lipopolysaccharide (LPS) found in most is_associated_with::gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness.

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 interact with:
 * is_associated_with::Lymphocyte antigen 96,
 * is_associated_with::Myd88,   and
 * is_associated_with::TOLLIP.

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.

Clinical Significance
Various single nucleotide polymorphisms (SNPs) of the TLR4 in humans have been identified and for some of them an association with increased susceptibility to Gram-negative bacterial infections or faster progression and a more severe course of sepsis in critically ill patients was reported.

Asp299Gly Polymorphism
Classically, TLR4 is said to be the receptor for LPS, however TLR 4 has also been shown to be activated by other kinds of lipids. is_associated_with::Plasmodium falciparum, a parasitic infection seen primarily in Africa, produces is_associated_with::glycosylphosphatidylinositol, which can activate TLR4. Two SNPs in TLR4 are co-expressed with high is_associated_with::penetrance in African populations (i.e. TLR-4-Asp299Gly and TLR-4-Thr399Ile). These Polymorphisms are associated with an increase in TLR4-Mediated IL-10 production—an immunomodulator—and a decrease in is_associated_with::proinflammatory cytokines. The TLR-4-Asp299Gly point mutation is strongly correlated with an increased infection rate with is_associated_with::Plasmodium falciparum. It appears that the mutation prevents TLR4 from acting as vigorously against, at least some plasmodial infections. The is_associated_with::Malaria infection rate and associated morbidity are higher in TLR-4-Asp299Gly group, but mortality appears to be decreased. This may indicate that at least part of the pathogenesis of is_associated_with::Malaria takes advantage of cytokine production. By reducing the cytokine production via the TLR4 mutation, the infection rate may increase, but the number of deaths due to the infection seem to decrease.

Animal studies
A link between the TLR 4 receptor and is_associated_with::binge drinking has been suggested. When genes responsible for the expression of TLR 4 and is_associated_with::GABA receptors are manipulated in rodents that had been bred and trained to drink excessively, the animals showed a "profound reduction" in drinking behaviours. Additionally, it has been shown that ethanol, even in the absence of LPS, can activate TLR4 signaling pathways.

High levels of TLR4 molecules and M2 is_associated_with::tumor-associated macrophages are associated with increased susceptibility to cancer growth in mice deprived of sleep. Mice genetically modified so that they could not produce TLR4 molecules showed normal cancer growth.

Drugs targeting TLR4
Toll-like receptor 4 has been shown to be important for the long-term side-effects of is_associated_with::opioid is_associated_with::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 is_associated_with::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 is_associated_with::hyperalgesia and is_associated_with::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 is_associated_with::enantiomer-independent, so the "unnatural" enantiomers of opioid drugs such as morphine and is_associated_with::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.

is_associated_with::Morphine causes is_associated_with::inflammation by binding to the protein is_associated_with::lymphocyte antigen 96, which, in turn, causes the protein to bind to Toll-like receptor 4 (TLR4). The morphine-induced TLR4 activation attenuates is_associated_with::pain suppression by is_associated_with::opioids and enhances the development of opioid tolerance and is_associated_with::addiction, is_associated_with::drug abuse, and other negative side effects such as is_associated_with::respiratory depression and hyperalgesia. Drug candidates that target TLR4 may improve opioid-based is_associated_with::pain management therapies.

Agonists

 * is_associated_with::Buprenorphine
 * is_associated_with::Carbamazepine
 * is_associated_with::Ethanol
 * is_associated_with::Fentanyl
 * is_associated_with::Levorphanol
 * is_associated_with::Lipopolysaccharides (LPS)
 * is_associated_with::Methadone
 * is_associated_with::Morphine
 * is_associated_with::Oxcarbazepine
 * is_associated_with::Oxycodone
 * is_associated_with::Pethidine


 * Glucuronoxylomannan from is_associated_with::Cryptococcus
 * is_associated_with::Morphine-3-glucuronide (inactive at opioid receptors, so selective for TLR4 activation)
 * "Unnatural" isomers such as (+)-morphine activate TLR4 but lack opioid receptor activity, although (+)-morphine also shows activity as a is_associated_with::sigma receptor agonist.

Antagonists

 * The is_associated_with::lipid A analog is_associated_with::eritoran acts as a TLR4 antagonist., it was being developed as a drug against severe is_associated_with::sepsis. However, in 2013, a news story said the results against sepsis were somewhat disappointing and that it was better used to treat certain cases of severe influenza, though it does not treat the virus itself but against the massive immune reaction called is_associated_with::cytokine storm which occurs later in the infection and, sometimes in concert with sepsis (it can also help cause sepsis), sometimes alone, can kill.


 * is_associated_with::Amitriptyline
 * is_associated_with::Cyclobenzaprine
 * is_associated_with::Ibudilast
 * is_associated_with::Imipramine
 * is_associated_with::Ketotifen
 * is_associated_with::Mianserin
 * is_associated_with::Naloxone
 * is_associated_with::Naltrexone
 * (+)-naltrexone
 * is_associated_with::Propentofylline
 * LPS-RS


 * (+)-naloxone ("unnatural" isomer, lacks opioid receptor affinity so selective for TLR4 inhibition)