TLR4 - cluster of differentiation 284

Toll-like receptor 4 (TLR4) often designated as CD284 (cluster of differentiation 284) is a class I transmembrane receptor belonging to the large homologous family of Toll like receptors. TLR4 expressed on the surface of immune system cells, is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and thus forms part of the innate immune response in mammals. (1) TLR4 was initially cloned as the human homolog of Drosophila Toll (dToll) and thus was first named hToll. Like all other members of the TLR family, TLR4 is composed of an extracellular domain containing multiple leucine-rich repeats (LRRs), a transmembrane region, and a cytoplasmic tail containing the conserved TIR domain. TLR4 maps to chromosome 9q32-33. It shows a high degree of similarity to dToll over the entire aminoacid sequence. The TLR4 sequence encodes an 839 aminoacid protein with 22 N-terminal LRR regions and a calculated molecular weight of 90 kDa. TLR4 is most closely related to TLR1 and TLR6 each with 25% overall aa sequence identity. Several transcript variants of this gene have been found, but the protein coding potential of most of them is uncertain.

In vivo, TLR4 mRNA is expressed as a single transcript, and found at highest levels in spleen and PBLs. (2, 3) Of the PBL populations, TLR4 is expressed by B cells, DCs, monocytes, macrophages, granulocytes, and T cells. Other reports suggest that TLR4 is only expressed in myelomonocytic cells and is highest in mononuclear cells. In vitro, TLR4 mRNA and protein expression is upregulated in THP-1 cells upon PMA-induced differentiation. TLR4 is moderately upregulated by autocrine IFN-γ, IL-1β. TLR4 mRNA expression in THP-1 cells is unaffected by exposure to both Gram-positive and Gram-negative bacteria. Ex vivo, granulocyte, and especially monocyte, TLR4 expression is upregulated upon exposure to Gram-negative bacteria. (4)

TLR4 is critical for host defense against gram-negative bacteria in both mice and humans. Upon recognition of its ligand LPS, TLR4 undergoes dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR) signalling domain. Ligand recognition by TLR4 requires the extracellular association of an additional component, MD-2 which together can initiate two major intracellular signaling pathways, MyD88-dependent and TRIF-dependent (MyD88-independent). The MyD88-dependent pathway requires the recruitment of TIRAP and MyD88 via homophilic TIR-TIR interactions and activates nuclear factor (NF)-κB, activator protein-1 (AP-1) and interferon regulatory factor 5 (IRF5), which induce inflammatory cytokine expression such as IL-6, IL-12, and TNFα. The TRIF-dependent pathway requires the recruitment of TRAM and TRIF and activates IRF3, in addition to NF-κB and AP-1, which induce type I interferon (IFN) expression. TLR4 can also activate various other signaling molecules, including phosphatidylinositol-3 kinase (PI-3K) and MAP3Ks such as MEKK3, TPL2, and ASK1. (5,6) The TLR4 complex also recognizes a few other bacterial PAMPs including LTA. Further, the TLR4 complex recognizes viruses including respiratory syncytial virus (RSV), hepatitis C virus (HCV), and mouse mammary tumor virus (MMTV). The TLR4 complex can also recognize endogenous ligands, for example, heat shock proteins, fibrinogen, fibronectin, surfactant protein A (SP-A), and β-defensins. TLR4 also forms heterodimers both with TLR5, which presumably enhances its activity, and also with TLR1, which inhibits its activity. (7, 8)

Mutations in TLR4 gene have been associated with differences in LPS responsiveness.
A recently discovered Asp299Gly TLR4 polymorphism has been identified that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide and is associated with a decreased risk of atherosclerosis. (9)

Reference:
1. Ricardo et al. PLoS ONE. 2007; 2(8): e788.
2. Medzhitov, R. et al. (1997) Nature 388:394.
3. Rock, F.L. et al. (1998) Proc. Natl. Acad. Sci. USA 95:588.
4. Zarember, K.A. and P.J. Godowski (2002) J. Immunol. 168:554.
5. Myeong Sup Lee Vol. 76: 447-480 Annual Review of Biochemistry
6. Yong-Chen Lu doi:10.1016/j.cyto.2008.01.006 Article in press
7. Spitzer, J.H. et al. (2002) Eur. J. Immunol. 32:1182.
8. Mizel, S.B. et al. (2003) J. Immunol. 170:6217.
9. N Engl J Med 2002; 347:1978-1980, Dec 12, 2002.

Listed below are more articles related to the above article from the "Alternative Medicine" article category.

People interested in the above article "TLR4 - cluster of differentiation 284" are also interested in the related articles listed below:

Neuropilin-1/BDCA-4/CD304

Neuropilin-1 (Nrp-1) was recently identified as a possible surface marker for naturally occurring CD4+CD25+ regulatory T cells and is constitutively expressed on the cell irrespective of its activation status.

Do You Need Chigger Bite Help, Tonight?

The chigger dance is not just a sport for newbies. Chiggers will take on all new and old challengers. The chigger offers great entertainment and compatition to young and old. Every chigger season a produces a new game of gladiators locked in mortal combat. The coliseum is the bedroom and the gladiator is a defenseless warrior.

Same Day Cash Loans: For Those Who Are In Need Of Quick Finances

Handling an emergency financial crisis at a time when you are plagued with sever financial crisis can be termed as one of the worst situation. In these circumstances, it will always be problematic to avail external finance. Same day cash loans turns out to be a reliable option when it comes to meeting your urgent needs. The amount under these loans gets approved in less than 24 hours. The loans are available for a short term period and are oprn to all the borrowers.

Cash Till Payday: A Loan Scheme For Your Stressful Economic Problems

It often happens, that even after decent financial planning and efficient budgeting; we fail to come up with fail to arrange for good monetary funds in times of urgent requirements. In fact, such kind of stressful situations mainly occur in the middle of our two consecutive paydays, where supporting any extra, heavy expense is totally impossible for a salaried individual.

Tarsal Tunnel Syndrome And Massage Therapy

Do you have foot pain or numbness? You could have a condition known as Tarsal Tunnel Syndrome. Massage Therapy and Bodywork are very effective in treating conditions arising from muscular and connective tissue abnormalities. In my San Antonio, Texas based Massage Therapy and Bodywork practice I often treat pain from various muscular and nerve entrapment syndromes including the supposedly rare Tarsal Tunnel Syndrome.

Chelation Therapy Has Been Approved by the FDA as a Treatment for Lead Poisoning

Chelation therapy is a natural way to detoxify the body of toxic chemical and harmful metals (heavy metal poisoning). Chelation therapy involves the injection of ethylene diamine tetraacetic acid (EDTA). It is a mean by which an organic substance (Edta) binds to minerals and ionized metals (electrically charged) such as iron, calcium, lead, copper, etc.

Take Care of Your Feet

Think about the part of your body that takes the most abuse every day. It doesn't matter if you are jogging at the park, running on the field, or walking around the office, each activity puts stress on a major part of your body. The parts of your body that take a beating everyday are your feet and ankles. No matter where you go or what you do, as long as you are walking, running, or jogging your feet and ankles are the parts of your body that pay the highest price. Without the proper preventative care, many athletes end up injuring themselves in their foot and ankle area.