from Park et al. Immunity (2005)

Ligands recognized by TLR4: TLR4 is the key receptor for most bacterial lipopolysaccharides such as Escherichia coli (Gram-negative bacteria) lipopolysaccharide (LPS). TLR4 detects Gram-negative bacteria through recongition of the lipid A moiety of bacterial lipo-polysaccaride (LPS). TLR4 also recognizes components of the bacillus Calmette-Guerin (BCG) strain of M. bovisand the respiratory syncytial virus (RSV). 

Signal Trasduction: As with TLR2 the binding is complex and involves the participation of three additional proteins, one of which is the lipopolysaccharide-binding protein (LBP). People with an underactive form of TLR4 are 5 times as likely to have several bacterial infections over a 5 year period than those with a normal TLR4. On the other hand, in the US and Europe more than 400,000 people die annually from sepsis, which stems from an overactive immune response led by TLR4.

LPS binds to LPS-binding protein and eventually to CD14 expressed on monocytes, macrophages and other host cells. Because CD14 lacks an intracellular signaling domain, interaction between CD14, TLR4 and MD2 is necessary to mediate an intracellular signal transduction. This signal results in production of cytokines such as IL-1B and TNF.

TLR4 can signal via both MyD88 and TRIF. TIRAP/Mal is an adaptor involved in coupling MyD88 to TLR4. MyD88 and TRIF together promote activation of NF-kB and MAPKs, allowing transcription of cytokine genes. TRIF also activates IRF3, leading to IFN? synthesis. IFN? then signals in an autocrine or paracrine manner via IFN-IR and STAT-1 to increase upregulation of B7-1, B7-2 and CD40. Thus signaling through TLR4 can activate the MyD88 independent pathway, leading to NF-kB activation. 

TRAF6 can activate ERK1/2, p38 JNK  but also activates TAK1 which activates NF-kB which can activate TNF.

Another transcription factor, IRF-3 activates Ifnbeta which activates TypeI IFNr which activates STAT1 which activate IP10.

Activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway and protein kinase C by TLR4 signaling has also been reported.

TLR4 signalling/MyD88 pathway:

An adaptor molecule MyD88 binds to TLR4. Upon stimulation, MyD88 recruits Il-1 receptor-associated kinase (IRAK) to TLR4. IRAK then activates TNFR-associated factor 6 (TRAF6), leading to activation of NF-kB and c-Jun N-terminal kinase.

Biological Responses Initiated: Interestingly E. coli LPS induces a Th1-type immune response and the production of IL-12, while P. gingivalis LPS induces Th2 type immune resposnes. 

One reported function of TLR4 signaling is regulation polymorphonuclear nuetorphil (PMN) migration by modulation of the cell surface epxression of chemokine receptors, indicating that corss talk between TLR4 and G protin-coupled receptors is a critical determinant of the host-defense response.

It has also been reported that LPS may induce TLR2 expression in human endothelial cells in an NF-kB dependent manner, suggesting a role of NF-kB in the possible cross talk between TLR2 and TLR4 signaling.

Inhibitors of TLR4: 

Several negative regulators of TLR signaling have been found includingSIGIRR, IRAK-M, MyD88s, Tollip, ST2, Nod2  Triad3A and RP105.