Figure 1

MyD88-dependent pathway. TLR4 uses CD14 to respond to LPS. LBP binds to LPS and presents it to CD14. MD2 is necessary for TLR4 to bind to LPS. MAL connects TLR4 and MyD88. Afterwards, MyD88 binds to IRAK4 and IRAK1/2. The IRAK complex then dissociates from MyD88 and interacts with TRAF6. TRAF6 forms a complex with TAK1, TAB1, and TAB2. Later, the complex binds to ubiquitin ligases, including UBC13 and UEV1A. TAK1 then activates the IKKα/IKKβ/IKKγ complex and induces IκB phosphorylation. Phosphorylated IκB dissociates from the complex and is directly targeted for ubiquitination and degradation by proteasomes, thus activating the transcription factor NF-κB. The released NF-κB translocates into the nucleus and mediates the expression of a number of pro-inflammatory cytokine genes. In addition to the activation of the IKK complex, TAK1 can activate MAPK signaling pathways, such as ERK, JNK, and the p38 pathway. MAPK signaling pathways can activate the transcription factor AP-1. Activation of NF-κB and AP-1 contributes to the expression of pro-inflammatory cytokines, such as IL-1, IL-6, and TNF-α. Notably, GP leads to TLR4 disassociating from MyD88, binding PI3K, further phosphorylating Akt and promoting survival and inhibits cardiac myocyte apoptosis. Gene names: ERK, extracellular signal-regulated kinase; GP, glucan phosphate; IKK, inhibitory κB (IκB) kinase; JNK, c-Jun N-terminal kinase; MAL, MyD88-adapter like; UBC13, ubiquitin-conjugating enzyme 13; UEV1A, ubiquitin-conjugating enzyme variant 1A